3-indolyl lower aliphatic amines



United States Patent US. Cl. 260240 8 Claims ABSTRACT OF THE DISCLOSURE The invention concerns S-indolyl lower aliphatic amines having an aroyl or heteroaroyl radical of less than three fused rings attached to the nitrogen atom of the indole nucleus. Also covered are novel intermediates for the preparation of the above compounds. These intermediates are the 3-indolyl nitro aliphatic compounds and 3- indolyl alkylimines having an aroyl or heteroaroyl radical of less than 3 fused rings attached to the nitrogen atom of the indole nucleus.

This application is a continuation of our co-opending application Serial No. 380,020 filed July 2, 1964, now abandoned.

This invention relates to new chemical compounds. More specifically, it relates to a new class of compounds of the indole series. Still more specifically, it is concerned with new 3-indolyl lower aliphatic amines having an aromatic carboxylic acyl (aroyl or heteroaroyl) radical of less than three fused rings attached to the nitrogen atom of the indole nucleus. The invention is also concerned with the acid salts of these novel amines, to novel inter-mediates for the preparation thereof, and to the synthesis of all these compounds.

The new aroyl and heteroaroyl indolyl aliphatic amines of this invention have the general structural formula:

I Ra

wherein:

R is selected from the group consisting of:

--JJ--(|JCH2 Ra Ra A I I 'ice the nitrogen, piperidino, 1,2,5,6-tetrahydropyridino, morpholino, N-methylpiperazino, piperazino, N-phenylpiperazino, pyrrolidino, and N-hydroxyethylpiperazino rings; R is selected from the group consisting of hydrogen, lower alkenyl, p-lower alkoxyphenyl and lower alkyl;

R, and R are selected from the group consisting of hydrogen, hydroxy, lower alkyl, lower alkoxy, nitro, amino, lower alkylamino, di(lower alkyl)amino, lower alkanoylamino, lower alkanoyl, bis(hydroXy lower alkyl) amino, l-pyrrolidino, 4-methyl-1-piperazinyl, 4-morpho-' linyl, cyano, trifluoromethyl, halogen, di(lower alkyl) sulfamyl, benzylthio, benzyloxy, lower alkylbenzyloxy, lower alkoxybenzyloxy, halogenobenzyloxy, lower alkenyl, lower alkenyloxy, l-azacyclopropyl, cyclopropyl lower alkoxy, cyclobutyl lower alkoxy, and when R, and R are ortho to each other and taken together, lower alkylenedioxy;

R may be an aromatic radical of less than three fused rings of more than four and less than seven atoms to the ring, in which rings any heteroatoms present are selected from the group consisting of oxygen, nitrogen, and sulfur, there being from zero to three such heteroatoms present in no more than one of said rings and in which aromatic radicals any substituents other than hydrogen are selected from the group consisting of halogen, lower alkyl, lower alkylthio, lower alkoxy, trifluoromethyl, phenoxy, lower alkylphenoxy, lower alkoxy phenoxy, halogenophenoxy, trifluoroacetyl, difluoroacetyl, di(lower alkyl)sulfamyl, lower alkanoyl, di(lower alkyl)carboxamido, cyano, carb-lower alkoxy, aldehydo, trifluoromethylthio, lower alkylsulfinyl, lower alkylsulfonyl, benzylthio, lower alkylbenzylthio, lower alkoXybenzylthio, halogenobenzylthio, mercapto, nitro, amino, di(lower alkyl)amino, lower alkylamino, lower alkanoylamino, hydroxy, lower alkanoyloxy, trifiuoroacetoxy, difiuoroacetoxy, benzyloxy, lower alkylbenzyloxy, lower alkoxybenzyloxy, and halogenobenzyloxy;

n is a number from 1 to 3; and their acid addition salts.

The preferred R groups in the compounds of this invention are (p w but especially the ethyl group. The preferred R groups are lower alkyl (methyl, ethyl, butyl, and the like), hydrogen, and p-lower alkoxyphenyl (methoxyphenl, propoxyphenyl, and the like), but especially lower alkyl (methyl). The preferred groups on the R, and R positions are lower alkyl (methyl, ethyl, butyl, and the like), hydrogen, methylene (when R, and R, are taken together), hydroxy (only for R,), and lower alkoxy (methoxy, ethoxy, butoxy, and the. likeonly for R,), but especially lower alkyl (methyl) or lower alkoxy (methoxy). The preferred groups on the R and R" positions are hydrogen, lower alkyl (methyl, propyl, butyl, and the like), lower alkenyl, (allyl, vinyl, and the like), hydroxy lower alkyl (hydroxymethyl, hydroxypropyl, and the like), ,3-phenethyl acetyl and a-phenethyl (only one of R and R" being fi-phenethyl acetyl or aphenethyl at any one time), but especially lower alkyl (methyl) and lower alkenyl (allyl). The preferred groups on the R position are hydroxy, fluorine, lower alkoxy (methoxy, propoxy, butoxy, and the like), and lower alkenyl (allyl, vinyl, and the like). The preferred groups on the R position are halogen (fluorine, chlorine or bromine), lower alkyl (methyl, ethyl, propyl, and the like), lower alkoxy (methoxy, ethoxy, propoxy, and the like), hydroxy, and lower alkenyl (allyl, vinyl, and the like), but especially hydroxy and lower alkenyl (allyl). When there is more than one substituent on the benzene ring, the preferred groups are 5,6-methylenedioxy, 5,6- dilower alkoxy (dimethoxy, diethoxy, and the like), 4,5,6- trilower alkyl (trimethyl, and the like), 5,6-dichloro, and 4,5,6-tribenzyloxy, but especially 5,6-methylenedioxy and 5,6-dilower alkoxy. The preferred groups on the R position are substituted phenyl groups wherein the phenyl is substituted with 0-, m-, or p-halo, lower alkoxy (methoxy, propoxy, and the like) and lower alkylthio (methylthio, propylthio, butylthio, and the like); trifluoromethyl, b,p-dilower alkoxy (dimethoxy, diethoxy, dibutoxy, and the like), m,p-dilower alkoxy (dimethoxy, dipropoxy, dibutoxy, and the like), o,m,-methylenedioxy, m,p-methylenedioxy, and 3,4,5- trilower alkoxy (trimethoxy, tripropoxy, tributoxy, and the like), but especially lower alkylthio (methylthio), lower alkoxy (methoxy), o,p-dilower alkoxy (dimethoxy), -rn,p-methylenedioxy, and 3,4,5-trilower alkoxy (trimethoxy).

We have found that when a 3-indolyl lower aliphatic amine is substituted in the N-l position by an aroyl or hetero-aroyl group such as p-chlorobenzoyl or 2-thenoy1 rather than by a lower alkyl group, the N-l acyl compounds produced possess anti-infiammatory activity, also exhibit anti-pyretic action, indicate value as anti-serotonin, analgesic, antidepressant, and psychic-stimulating agents and are also of value in the treatment of arthritic, dermatological disorders, and other like conditions which are responsive to treatment with anti-inflammatory agents.

For these purposes, the compounds of this invention are normally administered orally in tablets or capsules, the optimum dosage depending, of course, on the particular compound being used and the type and severity of infection being treated. Although the optimum quantities of these compounds of this invention to be used in such a manner will depend on the compound employed and the particular type of disease condition treated, oral dose levels of preferred compounds in the range of 1.0-2,000 mg. per day are useful in control of arthritic conditions, depending on the activity of the specific compound and the reaction sensitivity of the patient.

It is an advantage of our invention that substitution at the N-l position with an aroyl or hetero-aroyl group in a 3-indo1yl lower aliphatic amine compound imparts anti-inflammatory activity to the previously non-active compound.

The compounds of this invention also absorb ultraviolet light and are generally useful as sun-screening materials in salves and ointments. In addition, because of their high solubility in organic materials generally, they may be used as ultraviolet absorbers in plastics and resins, such as polystyrene, polyethylene, polypropylene, polyacrylics (methacrylate resins, polyacrylamides, polyacrylonitrile fibers), polyamide fibers (e.g., nylon), and polyester fibers. In this use, the inclusion of 0.01 to 5% of the absorber, based on the polymer weight, is sufficient to render protection against instability due to ultraviolet light. The absorber may be incorporated in the mixture of monomers before polymerization to form the polymer or it may be incorporated in the polymer at any stage during its handling, as by milling into the polymer together with other compounding ingredients or during the spinning of polymers into fibers, etc.

The basic indole structure for all the compounds of this invention, namely:

is readily prepared following known procedures such as those set forth in columns 2 and 3 of US. Patent No. 2,825,734. Products where R is acyloxy, halo, cyano, carboxy, carbalkoxy, N,N-dilower alkyl carbamyl, alkyl, aryl, aralkyl, nitro, or hydrocarbonoxy are prepared via the synthesis beginning from a substituted 2-nitro-benzaldehyde or 2-nitro-toluene.

The synthesis of various compounds of this invention having on the indole ring system an R or R -substituent which has a nitrogen attached to the homocyclic ring of the indole is generally based on the 4 0r S-nitro compound. This is transformed into the desired R or R substituent. Such transformation may be before or after acylation of the 1-position, depending on the extent to which the desired 4 or S-substituent may interfere with the acylation. If such interference is possible, the 1- acylation should be carried out on the 4 or S-nitro indole and the nitro later transformed into the desired 4 or 5- substituent. Such transformation can be carried out in a number of ways. Reduction of the 4 or S-nitro groups gives a 4 or S-amino group. Reaction of the amino with alkyl halides gives mono or dialkylamino groups. If the alkyl halide is a dihaloalkylene group (e.g., 1,4-dibromobutane), a heterocyclic ring (e.g., pyrrolidino) is formed. Similarly, bis (fl-chloroethyDether will give an N-morpholino compound. Alkylation can also be carried out simultaneous with reduction, as, e.g., with formaldehyde and Raney nickel and hydrogen. Acylation can similarly be carried out on the 4 or S-amino compounds or on the 4 or S-nitro (with simultaneous reduction) to give 4 or S-acylamido compounds. The 4 or S-amido group can be reacted with isocyanates to give 4 or S-ureido compounds. Free mercapto groups likewise will interfere with the acylation and should be formed after such a step or protected by conversion to an alkyl or aralkylthio group.

The prepartion of the starting materials for this invention differs depending on to which of three separate classes of indole compounds, namely, (1) methylamines, (2) ethylamines, and (3) propylamines, the final products will belong. It will be noted (Flow Sheets I, III, and V) that regardless of which class of starting material is prepared, N-l acylation and/or reduction is required. Under these circumstances for further clarity, a general discussion of the acylation and reduction steps is first given, which will apply to all classes of starting materials, followed by discussions, which, for the most part, pertain to each specific class at hand.

In those cases wherein the starting material contains the N-l-acyl group (such as Compounds II, III, V, VI, VII, VIII, X, and XI), the substituents on the indole ring and R, and/or R, which are susceptible to acylation (compounds containing active hydrogen, such as NH; and COOH) either must be eliminated or protected prior to acylation. In those cases wherein the indole substituent contains an amino group, the corresponding nitro group is used, and after acylation, the compound is reduced to the primary amine and subsequently treated to obtain the required substituted amino group. In those cases wherein the indole substituent contains the hydroxyl or carboxyl group, these groups may be protected prior to acylation by forming the benzyloxy substituent, which in turn, after acylation, may be reduced to the corresponding hydroxy or carboxy group.

In those cases wherein areduction is required to prepare the starting materials, Compounds I (prepared responding hydroxy or substituted hydroxy may be used, whereupon, after reduction, the benzyloxy substituent may be obtained by benzylating the hydroxy group. In cases wherein the substitution is the cyano group, the carboxamide group is used in its place, whereupon, after reduction, the carboxarnide is dehydrated to the desired cyano substituent. In some cases, it is also possible to reduce the particular compound by a selective reduction, which will not affect certain groups. Some of these reducing techniques are herein described with reference to the various starting materials of our invention:

When R and/or R" substituents are desired other than hydrogen (as, e.g., in Compounds I, IV, and IX), the primary amino group of these compounds is reacted with the proper organic halide to yield the desired R and/or R substituent, as, e.g., when a lower alkyl is desired, the primary amino group may be reacted with a lower alkyl iodide in an inert solvent at slightly elevated temperatures; when an allyl group is desired, the primary an allylamino group may be reacted with an allyl bromide; or when R and R" are taken together with the nitrogen and the morpholino group is desired, the reaction may be carried out on the primary amino group using 18,6-dichlorodiethyl ether.

(A) PREPARATION OF METHYLAMINE STARTING MATERIALS The starting materials used for the preparation of the methylamine compounds (Flow Sheet I) of this invention may be described as: N-l-unsubstituted-3-indolylmethylamines (Compound I); N-l-acyl-indoles (Compound II); and N-1-acyl-3-indolylmethylimines (Compound III).

Nl-unsubstituted-3-indolylmethylamines This compound may be prepared by a Mannich reaction between the corresponding indole, formaldehyde, and a secondary amine, or an N-unsubstituted cyclic amine, usually as the hydrochloride (Step 1). When a primary amine is desired on the side chain, dibenzylamine is used in the above reaction, and when a secondary amine is desired on the side chain, a benzylalkylamine isused. In either case, the primary or secondary amine is subsequently obtained by reducing the benzylamine group at any stage of the synthesis, by any known means. Compound I with an R, substituent other than hydrogen may be prepared by reducing the imine (Step (6)) obtained from Step (4) and subsequent reaction of. the primary amine thus obtained to provide the desired R and R" substituents.

N1-acyl-indoles This compound may be prepared by acylating the corresponding indole with an anhydride or halide of an aroic acid or hetero-aroic acid or an ester of oand/ or p-nitrophenol and an aroic or hetero-aroic acid, in the presence of a strongly basic condensing agent, such as 'NaH, in an inert solvent at ambient temperatures (Step (2) N-l-acyl-3 -indolylmethylimines This compound may be obtained by first preparing the 3-indolyl aldehyde by reactinng the corresponding indole with phosphorous oxychloride and dimethylformamide or ethylmagnesium bromide and ethyl formate (where R3 is to be hydrogen) or using ethylmagnesium iodide and an acid chloride (RCOCl) when R, is to be other than hydrogen (Step (3)). The 3-indolyl aldehyde or ketone is then reacted with a primary amine to form an N-l-unsubstituted-3-indolylimine (Step (4)). This imine is then acylated as in the preparation of Compound II.

6 FLOW SHEET 1 Preparation of methylamine starting materials (III) EquivalentS.The various substituents are as previously defined.

Reactions and conditions Step (1).Reaction with formaldehyde and dibenzylamine, benzylalkylamine or a secondary amine of the formula in an inert solvent, such as ethanol (Mannich reaction). (In this case R,=hydrogen). When dibenzylamine or benzylalkylamine is used, the product thus obtained after the Mannich reaction is reduced by any known means (such as palladium on charcoal).

Step (2).Reaction at room temperature with an anhydride or chloride of an aroic acid or hetero-aroic acid of 0- and/or p-nitrophenyl ester of an aoric or heteroaroic acid in the presence as NaI-I in an inert solvent, such as dimethylformamide.

Step (3).-Reaction with chloroform and alkali (used when R,, is H) or reaction with an aliphatic acid anhydride at elevated temperatures (used when R, is other than H) in an inert solvent or in the acid anhydride itself acting as the solvent.

Step (4).--Reaction with the desired primary amine in an inert solvent or in the amine itself acting as solvent at room temperature.

Step (5 ).Same as Step (2).

Step (6 ).Reduction with palladium on alumina in an atmosphere of hydrogen in an inert solvent at room temperature.

The reduction of the imine in the preparation of Compound I may be carried out by a catalytic reduction, 8. sodium and alcohol reduction, or a zinc and acetic acid reduction. When a benzyloxy, alkenyl, alkynyl, cyclopropyl, or benzylthio group is desired in Compound I, the reduction step (Step (6)) may be carried out in the presence of sodium and alcohol, thereby not affecting the said groups. In those cases wherein it is desired to retain an aldehyde group, reduction may be carried out with zinc and acetic acid.

FLOW SHEET II Preparation of methylamine compounds of this invention (III) Equivalents: The various substituents are as previously defined.

Reactions and conditions Step (1).Reactions with formaldehyde and dibenzylamine, benzylalkylamine, a secondary amine, or N-unsubstituted cyclic amine at any suitable temperature and time, using the formaldehyde or amine as a solvent or an inert solvent such as acetic acid, alcohols, and the like. When dibenzylamine or benzylalkylamine is used, the reaction product is subsequently reduced, by known means (such as palladium on charcoal) to obtain the primary or secondary amine.

Step (2).Reaction with a mixed anhydride of an aroic acid or hetero-aroic acid and a strong inorganic acid or a mixed anhydride of an aroic acid or hetero-aroic acid and an organic acid or ester of an aroic acid and oand/ or p-nitrophenol or a hetero-aroic acid and and/or pnitrophenol (preferably an aroic acid anhydride or halide, especially p-methylthiobenzoyl chloride or p-chlorobenzoyl chloride) in a suitable solvent (such as dimethylformamide, benzene, toluene-dimethylformamide preferred) in the presence of a strongly basic condensing agent (such as sodium hydride and potassium hydridesodium hydride preferred) at any effective combination of temperature and time (preferably room temperature for one hour).

Step (3 ).-Reduction by catalytic reduction, metal acid reduction, or diborane reduction followed by reaction of the amine thus formed with an organic halide when additional substituents are desired on the amine. (See col. 5, line 12 to line 24.)

Step (2) may be carried out under Mannich reaction conditions. The formaldehyde is generally used in the form of 20-40% aqueous solution. The reaction is preferably carried out in an alcoholic solvent (e.g., methanol, ethanol, and the like) containing a trace of a hydrohalic acid, although water, acetic acid, and mixtures of acetic acid and water may be conveniently employed. The reaction is usually carried out at temperatures between 10'50 C., preferably at ambient temperatures. The time of the reaction may be from 15 minutes to overnight, preferably longer than one hour. When a primary amine is desired, dibenzylamine is used. When an R or R" substituent is desired other than hydrogen, a benzylalkyl amine is used, and in those cases wherein both R and R are to be other than hydrogen, a secondary amine or cyclic amine is used. Subsequently, the dibenzylamine or benzylalkylamine is reduced. It is to be observed that this procedure to prepare the methylamine compounds of our invention is used only when R, is to be hydrogen. In those cases wherein R, is to be other than hydrogen, the other indicated processes are to be used.

(B) PREPARATION OF ETHYLAMINE COMPOUNDS The starting materials used for the preparation of the ethylamine compounds (Flow Sheet III) of this invention may be described as: N-1-unsubstituted-3-indolylethylamines (Compound IV); N-1-acyl-3-indolylnitroethenes (Compound V); N-1-acyl-3-indolylethylimines (Compound VI); and N-l-acyl-3-indolylacetonitriles (Compound XI).

N-l-unsubstituted-3-indolylethylamines and N-l-acyl-3-indolylnitroethenes These compounds may be prepared by similar procedures. An N-l-unsubstituted-3-indolylnitroethene is first prepared (Steps (7) and (8)). These compounds may be prepared as indicated in column 5, line 4, of US. Patent No. 3,072,530. The procedure in the patent describes the preparation of a straight chain nitroethene compound. However, by a slight modification of reactants, the nitroethene compounds for the instant application can be prepared. For example, in those cases wherein an R, other than hydrogen is desired, the corresponding indolyl ketone rather than the indolyl aldehyde is used, and when an R, other than hydrogen is desired, the corresponding nitroalkane is used. After preparing the N-l unsubstituted-3-indolylnitroethene as described above, Compound IV is prepared by reducing the said N-l-unsubstituted-3-indolylnitroethene, and, if desired, subsesuent reaction of the primary amine thus obtained to provide the desired R' and R" substituents. Compound V is prepared by acylating the said N-1-unsubstituted-3-indolylnitroethene (as described in the prepartion of Compound II).

N-l-acyl-3-indolylethylimines This compound may be obtained by first preparing the indolyl acid corresponding to the final indolyl amine compound desired. This acid may be prepared by foll0wing the procedure set forth in Belgian Patent No. 615,395. The indolyl acid is then reacted with PO1 to prepare the corresponding acid chloride (Step (11)), which is then reacted with an organic cadmium compound to produce the corresponding indolyl ketone (Step (12)). The indolyl imine (Compound VI) is then prepared by reaction with a primary amine (following the procedure in Belgian Patent No. 628,441), and subsequently acylating the N-1 position.

N-l-acyl-3-indolylacetonitriles This compound may be prepared via the corresponding indole acetic acid. This may be accomplished by: (a) reaction of the N-1-unsubstituted indole acetic acid with triethylamine and isobutyl chloroformate followed by the addition of ammonia to produce the N-l-unsubstituted-Ia- 9 indolylamide (Step (25)) (b) acylating the indole amide thus formed (Step (26)); and (c) reaction of this N-lacyl amide with thionyl chloride in pyridine (Step (27) FLOW SHEET III Preparation of ethylamine starting materials (2) Ethylamines Equivalents: The substituents are as previously defined.

Reactions and conditions nitroalkane as the solvent.

Step (9).Same as Step (2), Flow Sheet I.

Step (10).-Reduction with lithium aluminum hydride. The reaction is usually carried out in an inert solvent, such as tetrahydrofuran, at slightly elevated temperatures. When R and/or R" other than hydrogen is desired, the primary amine thus obtained is reacted with the corresponding organic halide to obtain the desired substituent on the R and/or R".

Step (11).Reaction with phosphorus pentachloride at 0 C. in dry ether for approximately 3 hours.

Step (12 ).-Reaction with a di-aliphatic cadmium compound in an inert solvent, such as benzene, at the reflux temperature of the solvent for 1-2 hours. (The dialiphatic group of the cadmium compound corresponds to the desired R Step (13).Reaction with ammonia or with the desired primary amine in an inert solvent or in the amine itself acting as the solvent at room temperature.

Step (14).Same as Step (2), Flow Sheet I.

Step (25 ).Reaction in a suitable solvent at the temperature of the reaction mixture with a /2 ester of phosgene and a lower alkanol or a /2 ester of phosgene and an ar-lower alkanol to form an anhydride and subsequently adding ammonia.

Step (26).Sa1ne as Step (2), Flow Sheet I.

Step (27).Reaction with thionyl chloride in a suitable solvent at or below ambient temperatures.

In the preparation of Compound IV, three general reducing methods may be employed, namely, lithium aluminum hydride, metal acid, or a catalytic reduction, When it is desired to retain any alkenyl, alkynyl, cyclopropyl, and aldehyde groups in Compound IV, the reduction may be carried out with a metal acid. When it is desired to retain the benzylthio group, the reduction may be carried out directly with a metal hydride.

Compound VI is prepared from a corresponding N-lunsubstituted-3-indolyl acetaldehyde compound (Flow Sheet III, Step (12)). This aldehyde compound is prepared from the corresponding acid by conversion through the acid chloride (Flow Sheet IH, Steps (11) and (12.)). The conversion of the acid to the acid chloride will affect such groups as hydroxy, carboxamido, carboxy, amino, aldehyde, and keto; therefore, these groups must be either protected or eliminated prior to the acid chloride preparation. Protection of such groups as hydroxy, amido, amino, and carboxyl may be obtained by benzylating these groups prior to the preparation of the acid chloride, and, if desired, subsequently reducing the compound to obtain the said hydroxy, amido, amino, or carboxyl group.

The acylation, Step (26), in the preparation of the N-1-acyl-3-indolylacetonitrile compound may be carried out upon the amide as indicated, or the nitrile, Step (27), may be prepared from the N-l-unsubstituted amide followed by acylation of the nitrile formed. It is apparent then that the acylation may be carried out at either the amide stage 01 nitrile stage in the preparation of Compound XI. Reaction step (25) may be run With a /2 ester of phosgene and a lower alkanol or ar-lower alkanol; such alcohols may be represented as ethanol, propanol, isobutanol, benzyl alcohol, and the like, isobutanol being preferred. Any inert solvent may be used which will dissolve the reactants; such suitable solvents are dimethoxyethane, dioxane, tetrahydrofuran, ethers, and the like, di-

methoxyethane being preferred. The temperature of the reaction is maintained no higher than the temperature created by the reaction, but preferably the reaction is carried out at or below ambient temperatures. The time of the reaction is determined by the nature of the reactants and the solvents employed. Step (27) is carried out at or below ambient temperatures, the reaction not being a lowed to be run much above ambient temperatures; in fact, ambient temperatures are preferred. Although other dehydrating agents may be used, thionyl chloride is the one of choice. Solvents that are inert to the reaction and which have basic characteristics such as pyridine may be used.

FLOW SHEET IV Preparation of the ethylamine compounds of this invention helm-1M H N R2 Equivalents: The substituents are as previously defined.

Reactions and conditions Step (1).-Same as Step (1), Flow Sheet II.

Step (3).Same as Step (3), Flow Sheet II.

Step (4 ).Reduction by catalytic reduction or metal acid reduction followed by reaction of the primary amine thus formed with the appropriate aliphatic halide when a secondary or tertiary amine is desired.

Step (5 ).Reduction by catalytic reduction, metal acid reduction, or diborane reduction followed by reaction of the primary amine thus formed with the appropriate aliphatic halide when a secondary or tertiary amine is desired.

(C) PREPARATION OF PROPYLAMINE STARTING MATERIALS to obtain the hydroxyethyl compound (Step 15)). The hydroxyethyl compound in turn is reacted with phosphorus bromide to yield the corresponding ethyl bromide compound (Step (16)), which in turn is treated with potassium cyanide to yield the above-mentioned N-1-unsubstituted 3 -indoly1propionitrile compound (Steps (15), (16), and (17)).

N-l -acyl-3-indolylpropionitriles This compound is prepared by acylating the said N-lunsubstituted 3 indolylpropionitrile compound (Step N-1-unsubstituted-3-indolylpropylamines This compound is prepared by reducing the said N1- unsubstituted-3-indolylpropionitrile compound to the primary amine and, when desired, appropriate reactions with the primary amine to obtain the substituted amines (Step (18)).

N-l -acy1-3-indolylpropylimines This compound is then prepared by reducing the said N-1-unsubstituted-3-indolylpropionitrile compound to the corresponding aldehyde by reduction with Raney nickel and sodium hypophosphite in aqueous acetic acid (Step (20)), The aldehyde thus obtained is treated with a primary amine- (in accordance with the procedure outlined in Belgian Patent No. 628,441) to produce the corresponding N1-unsubstituted 3 indolylirnine compound (Step (21)), which in turn is acylated (under conditions as previously mentioned to obtain Compound X) (Steps (20), (21.), and (22)).

N-l-acyl-3 -indolylnitropropenes This compound maybe prepared by reacting the corresponding N1-unsubstituted 3 -indo1y1ethy1ketone (obtained from Step 12)) .with nitromethane in accordance with the procedure described in US. Patent No. 3,072,- 530, column 5, line 4, to obtain the N-l-unsubstituted- 3-indoly1nitropropene and subsequently acylating this compound (Steps (23) and (24)).

13 14 FLOW SHEET V Preparation of propylamine starting materials I r Illa Illa Rs Ilia R5 CHC=NR Ryco=o R (Lo-0H 4)n" l I t T) 1'1 t 1./ R2

A R2 (3:0 H H I ia (X) Xe l! R5 R11 R5 1 1. R5 h o=o Rr tam 15 (R4). I l (Ron I 1's n A I E/\ H (17 20 23 I CHQNOZ a et r z r ta RF o-o=o-No R5/\I-- C-OH-CN 25 (R4)n on II I \IIIARZ H R;- CJJ=CNO2 R Ru H R R I I R5 hH-orL-m-N (R4)n (19) N R2 I R2 1' (VIII) Equivalents: The substituents are as previously defined i g Reactions and conditions R;, H H-ON (B4) I Step (15).Reaction With 5% palladium on charcoal in ethanol under an atmosphere of hydrogen at room temperature until reduction 1s complete.

Step (16).-Reaction with phosphorus tribromide in chloroform at room temperature for several hours. (VII) Step (17).Reaction with potassium cyanide in 90% R R1 H ethanol at the reflux temperature of the solvent for 1-3 115* JH-( JH&=O hours- Step (18).React1on W1th 10% palladium on charcoal in ethanol at room temperature in the presence of an N I atmosphere of hydrogen until reduction is complete. l I Step (]9).Same as Step (2),Flow Sheet I.

Step (20).-Reaction with sodium hypophosphite and a H Raney nickel in 75% acetic acid at slightly elevated temm w peratures for several hours. (R4),. I II: Step (21 ).Same as Step (13), Flow Sheet III. t R2 Step (22).Same as Step (2), Flow Sheet I.

N/ Step (23).-Reaction with nitromethane. The reaction I is carried out at elevated temperatures, usually using nitromethane as the solvent. I

Step (24).Same as Step (2), Flow Sheet I. Compounds VII, VIII, IX, and X are prepared from I ft T 5 the corresponding N-1-unsubstituted-3-indoly1 ketone 3 CHOHC=NR compound (Flow Sheet III, product of Step (12)). This I I ketone compound is prepared from the corresponding acid R by conversion through the acid chloride (Flow Sheet III, Steps (11) and 12)). The conversion of the acid to the V acid chloride Will aflect such groups as hydroxy, carbox- I amido, carboxy, amino, aldehydo, and'keto; therefore,

( these groups must be either protected or eliminated prior to the acid chloride preparation. Protection of such groups as hydroxy, amido, amino, and carboxyl may be obtained by benzylating these groups prior to the preparation of the acid chloride and, if desired, subsequently reducing the compound to obtain the said hydroxy, amido, amino, r carboxyl group.

The reduction of the nitrile in the preparation of Compound IX may be carried out using a catalytic reduction, a metal acid reduction, a sodium and alcohol reduction, a metal hydride reduction, or a diborane reduction; there fore, when it is desired to have a benzyloxy, alkenyl, alkynyl, cyclopropyl, and/or benzylthio group on Compound IX, the reduction may be carried out with sodium and alcohol and the said groups will not be aifected. When the substituent on the compound is to be an aldehydo group, a metal acid reduction may be used. When it is desired to retain any nitro group which may be present, the nitrile reduction may be carried out with diborane.

As indicated, Compounds VII, IX, and X are prepared from a common propionitrile compound. This propionitrile compound may be prepared from the ketone indicated in Steps (15), (16), and (17). The reaction for the conversion of the corresponding alcohol to the bromide compound (Step (16)) (the precursor of the said propionitrile compound) will also afiect any active hydrogen groups on the molecule. Therefore, when a hydroxy, amido, amino, or carboxyl group and the like is desired, it may be protected by benzylation prior to the PBr reaction and subsequently reduced to obtain the said hydroxy, amido, amino, or carboxyl group.

FLOW SHEET VI Preparation of the propylamine compounds of this Equivalents: The substituents are as previously defined.

Reactions and conditions Step (1 ).-Same as Step (1), Flow Sheet II.

Step (3) .-Same as Step 3), Flow Sheet I.

Step (4).Same as Step (4), Flow Sheet IV.

Step (5 ).Same as Step (5), Flow Sheet IV.

In the preparation of the compounds of this invention, several of the processes involve acylation, reduction, and/ or alkylation of an amine. Under these circumstances, because of various substituents on the indole ring, interference with the above-mentioned reactions may take place. When acylation is required, as, for example, the reactions of Compounds I, IV, and IX, a similar procedure is followed, as previously indicated, for the preparation of the N-l-acyl starting materials. In those cases where reduction is required to prepare the compounds of this invention, such as in the reaction of Compounds III, V, VI, VII, VIII, X, and XI, all those groups on the indole ring which are susceptible to reduction, such as nitro and cyano groups, must be either eliminated, protected, or in some cases particular reducing methods used Which will reduce the group desired but not others. In those'cases where the substituent on the ring is an alkenyl or alkynyl group, the corresponding aldehyde or ketone may be used, whereupon after reduction the aldehyde or ketone is converted to the alkenyl group by means of a Wittig reaction. (This procedure may be employed, however, only when the reduction is carried out with a metal acid.) Generally, when the reducible substituent on the ring is the nitro group, protection of this group from reduction is not easily attainable. However, reduction of Compounds III, VI, VII, X, or XI may be carried out without affecting any nitro group present by reducing with diborane. In those cases wherein the final compound is to contain a cyano on the ring and reduction is required to obtain the compounds of this invention-such as reactions of Compounds III, V, VI, VII, VIII, X, and XI-the carboxamide group may be used in place of the cyano group and after reduction the carboxamide group dehydrated to the desired cyano substituent.

In those cases wherein acylation is required to prepare the compounds of our invention, stoichiometric quantities of indole, metal hydride, and anhydride are advantageously employed. Among anhydrous organic solvents operable herein are the dialkylformamides (such as dimethylformamide, diethylformamide, and the like) aromatic hydrocarbons (such as benzene, toluene, xylene, chlorobenzene, nitrobenzene, and the like), mixtures of said dialkylformamides, and said aromatic hydrocarbons, tertiary butanol, and ethers (such as diethyl ether, 1,2- dimethoxyethane, tetrahydrofuran, and diphenyl ether). Other strong bases that may be advantageously utilized in lieu of the preferred alkali metal hydrides mentioned previously are alkali metal amides (such as sodamide, lithamide, and the like) and alkali metal tertiary alkoxides (such as sodium tertiary butoxide, potassium tertiary butoxide, and the like). An alternative method of acylating the 1-position is by use of a phenolic ester of the acylating acid, such as the p-nitrophenyl ester. The latter is prepared by mixing the acid and p-nitrophenol in tetrahydrofuran and adding dicyclohexylcarbodiimide in tetrahydrofura-n slowly. The dicyclohexyl urea which forms is removed by filtration and the nitrophenyl ester is recovered from the filtrate. Whichever is used, the acylation is achieved in either case by employing a strongly basic condensing agent, such as metal hydride.

If it is desired, various reducing agents may be used which are selective in the groups which they are capable of reducing. The reducible groups contemplated in our invention may be described as benzyloxy, alkenyl, alkynyl, cyclopropyl, nitro, cyano, benzylthio, and aldehydo. In those cases where a catalytic reduction may be employed, the benzylthio group will not be affected by this reduction. It a metal acid reduction is possible, alkenyls, alkynyls, cyclopropyl, and aldehydo groups are not affected.

In Steps (3) and (Flow Sheets II, IV, and VI), the respective imine and cyano group may be reduced FLOW SHEET VII to the amino group by catalytic, diborane, or metal acid reduction. In Step (4) (Flow Sheets IV and VI), the Preparatlon of Intermediates nitroalkene group may be reduced to the amino group 5 by catalytic or metal acid reduction. The catalytic re- R R duction may be carried out using a noble metal or nickel f (120%) in an atmosphere of hydrogen, preferably pal- R5 CH CHCN R5 ladium or platinum (540%) in an inert solvent (such as (R4) "g1 (R4)n I alcohols, ethyl acetate, dioxane, ethers, dimethyl- R2 formamide, and combinations of the same with acids), l preferably, however, alcohols and especially lower H H alkanols. Any convenient temperature may be used (room l (1) l (1) temperature to 100 C.). It is preferred, however, to use temper iagures bellow 315 5, especially ambient emperba- R Ra R R.

ures. e meta aci re uction may e carrie out y using a metal whose potential is above that of hydrogen 3 A CH CH CN plus a lower aliphatic acid or mineral acid (such as iron, 4 n R 4) tin, zinc, with hydrochloric acid, sulfuric acid, phos- N 2 phoric acid, formic acid, acetic acid, or the like), prefer- 0 (3:0 ably zinc and acetic acid. In addition, when necessary, I inert organic solvents may be employed which are capable of dissolving the reactant. The reaction may be carried R H out at any convenient temperature (room temperature to A l l 100 C.), preferably above 75 C., but especially at R5 (|7 C CNOZ steam-bath temperatures. The diborane reduction may be moti H carried out in such solvents as tetrahydrofuran (THF), A diglyme, ethers, and the like, preferably THF. Generally, 2 0.5 mole of diborane is added to the solvent containing the reducible compound; however, more or less diborane l (1) may be employed with only subsequent changes in yields. The reaction is normally run at ambient temperatures, but R Rs H any convenient temperature may be used (540 C.). R5 The reaction time depends upon the temmrature, solvent, l and reactivity of the reducible compound; generally, how H ever, 1-2 hours is a sufficient reaction time. As indicated N R2 previously, the diborane reduction is of particular ad- 4; vantage when the reactant contains a nitro group, which, I under these conditions, will not be reduced. However, groups such as alkenyl, alkynyl, and aldehydo are susceptible to diborane reduction. R5 RFNR, f

In Steps 2 3 4 and 5 (Flow Sheets II, IV, (R. I

and VI) when further substitution on the amino group is /R2 H desired, the reaction may be carried out by dissolving the reactants in an inert solvent such as dimethylformamide, ethers (diethyl ether and the like), ethyl acetate, alcohols (menthanol, propanol, heptanol, and the like), benzene, I (1) toluene, hydrocarbons, and the like, preferably, however,

alcohols]. The alkylating agent used may be any mono or dihalide which will afford the desired substituent on w Ri=NR C the R and/ or R group. The reaction temperature may i vary from 0 C. to the reflux temperature of the solvent, H and the reaction time will vary, depending upon the re- I R:

activity of the reactants, the temperature, and the solvents employed. Preferably, the alkylation is carried out in a R0 lower alcohol (ethanol) in the presence of an inorganic base (such as Na CO at the reflux temperature of the solvent for several hours.

The salts of the various amine compounds of our invention may be prepared from the amines in accordance with well-known procedures, as, e.g., dissolving the amine in a suitable organic solvent followed by the addition of the desired acid. If the hydrochloride is desired, the gaseous hydrochloric acid may be bubbled into the amine solution, whereupon precipitated hydrochloride is filtered and washed with an organic solvent (ethanol). Such salts, derived from hydrochloric acid, sulfuric acid, phosphoric acid, tartaric acid, citric acid, lactic acid, acetic acid, sulfamic acid, and like non-toxic acids are within the con templation of our invention.

The preparataion of the intermediates are indicated in Flow Sheet VII. The reactions and conditions have already been described.

Equivalents: Same substituents as previously defined.

The following examples are given by way of illustration.

EXAMPLE 1 2-methyl-3 -N,N-dimethylaminomethyl-S-methoxy indole To a solution of 0.02 mole of 2-methyl methoxy indole, 0.22 mole of dimethylamine, and a trace of concentrated hydrochloric acid in 250 ml. of ethanol is added 0.22 mole of 40% formaldehyde and the reaction refluxed for 5 hours. The solution is then cooled and filtered. The precipitated amine hydrochloride salt is dissolved in water and cautiously neutralized with 2.5 N sodium hydroxide. The solution is then extractedwith {3X 150 ml.) ether and the ether extract evaporated to yield 2 methyl 3 N,N-dimethylaminomethyl 5- methoxy indole.

When dibenzylamine, benzylethylamine, di(ethoxy) ethylamine, di(benzyloxy)ethylamine, hydroxyethylamine, di(hydroxypropyDamine, cyclopropylmethyl amine, cyclobutylmethylamine, piperidine, tetrahydrofurfurylamine, l,2,5,6-tetrahydropyridine, morpholine, N methylpiperazine, piperazine, N phenylpiperazine, cyclohexylamine, pyrrolidine, N hydroxyethylpiperazine, prop 2 en amine, but -2 yn amine, 2 methoxyethylamine, and benzyloxyethylamine are used in place of dimethylamine in the above example, there is obtained the corresponding 2 methyl 3 N substituted-aminomethyl 5 methoxy indole. (The aminomethyl or ethylaminomethyl compound is prepared from the dibenzylaminomethyl or benzylethylaminomethyl compound proiuced 'by using dibenzylamine or benzylethylamine, above, by reducing the said compound in the presence of palladium and charcoal.)

Similarly, when 2 methyl 4 methyl 5 methyl indole, 2-methyl-7 -rnethy1 indole,

2- (prop-2-en) -4-benzyloxy indole, Z-methyl-S-benzyloxy indole, 2-methyl-4ethoxy-5-methoxy indole, 2-methyl-4-nitro-S-methoxy indole, Z-methyl-S-nitro indole, 2-methyl-4-benzylideneamino-S-ethoxy indole, 2-methyl-5-benzylideneamino indole, 4-benzylideneaminoethyl-S-methoxy indole, Z-methyl-5-benzylideneaminoethyl indole, 2-methyl-4-di(ethyl) amino indole, 2-methyl-5-di(propyl) amino indole, 2-methyl-4-acetamido-5-propoxy indole, Z-methyl-S-acetamido indole, 4-acetyl-5-methyl indole, 2-methyl-4-p-methoxyphenyI-S'acetyl indole, 2-methy1-4-di (benzyloxyethyl) amino indole, 2-methyl-5-di (benzyloxypropyl) amino indole, 2-methyl-4- 1'-pyrrolidino) -5-methyl indole, 2-rnethyl-5-( 1'-pyrrolidino) indole, 2-propyl-4-(4'methyl-1'piperazinyl)indole, 2-propyl-5 4'-methy1- 1 '-piperazinyl) indole, 4-.(4'-morpholinyl) indole, Z-methyl-S-(4'-morpholinyl) indole, 2-methyl-4-cyano-5-methoxy indole, 2-methyl-4-methyl-5-cyano indole, 2-methyl-4-trifluoromethyl-S-methoxy indole, 2-methyl-5-trifiuoromethyl indole, 2-methyl-4-chloro-5-methoxy indole, 4-methyl-5-chloro indole,

4-bromo indole,

2-propyl-5-bromo indole,

2-methyl-4-fiuoro indole,

2-methyl-5-fluoro indole, 2-methyl-4-dimethylsulfamyl indole,

5 -dimethylsu1famyl indole, Z-methyl-4-benzylthio-5-methoxy indole, 2-methyl-4-methyl-S-benzylthio indole, 2-methy1-7-chloro indole,

7chloro indole, 7-methyl indole,

6-fluoro indole,

2-methy1-5 benzylthio indole,

2-methyl-4-benzyloxy-5-methyl indole,

Z-methyl-S-benzyloxy indole,

2-methyl-4-p-ethylbenzy1oxy indole,

2-methyl- 5-p-ethylbenzyloxy indole,

2-methyl-4-p-bromobenzyloxy-S-methyl indole,

2-methyl-S-p-chlorobenzyloxy indole,

4-allyl indole,

5-allyl indole,

4-(prop-2-enoxy)-5-methoxy indole,

2-methyl-5-(prop-2'-en0xy) indole,

2-methyl-4-(1-azacyclopr0pyl) indole,

5-( l'aazacyclopropyl) indole,

4-cyclopylmethoxymethyl-oxy indole,

5-cyclopropylmethoxymethyloxy indole,

2-methyl-4-cyclobutylethoxymethyloxy-5 -rnethy1 indole,

2-methyl-4-methyl-5-cyclobutylethoxymethyloxy indole,

2-methyl-4-dimethylsulfamyl-S-methoxy indole,

Z-methyl-S-dimethylsulfamyl indole,

2-methyl-4,S-rnethylenedioxy indole,

Z-methyl-S,6-methylenedioxy indole,

2-methyl-5,-6-diethoxy indole,

2-methyl-5,6-dichloro indole,

Z-methyl-S-dimethylamino indole, and

2-methyl-4,5,6-tribenzyloxy indole are used in place of 2-methyl-5- methoxy indole in the above example, there are obtained,

2-methyl-3-N,N dimethylaminomethyl 4 methyl-5- methyl indole,

Z-methyl 3 N,N-dimethylaminomethyl 7 methyl indole,

2 (prop-Z-en) 3 N,N dimethylaminomethyl 4- benzyloxy indole,

2-methyl 3 N,N-dimethylaminomethyl 5 benzyloxy indole,

Z-methyl 3 N,N-dimethylaminomethyl 4 ethoxy-S- methoxy indole,

2-2-methyl-3-N,N-dirnethylaminomethyl-4-nitro- S-metho-xy indole,

2-methyl 3 N,N-dimethylaminomethyl 5 nitro indole,

Z-methyl 3 N,N-dimethylaminomethyl-4-benzylideneamino-S-ethoxy indole,

2-methyl-3-N,N-dimethylamin0methyl 5 'benzylideneamino indole,

3 N,N-dimethylaminomethyl 4 benzylideneaminoethyl 5 methoxy indole,

2-rnethyl-3-N,N-dimethylaminornethyl-S-benzylideneaminoethyl indole,

2-methyl 3 N,N-dimethylaminomethyl 4 di(ethyl) amino indole,

Z-methyl 3 N,N-dimethylaminamethyl-S-di(propyl)- amino indole,

2-rnethyl 3 N,N-dimethylaminomethyl 4 acetamido- S-propoxy indole,

2-methyl 3 N,N-dimethylaminomethyl 5 acetamido indole,

3 N,N-dimethylaminomethyl 4 acetyl 5 methyl indole,

2-methyl 3 N,N-dimethylaminomethyl 4 p methoxyphenyl 5 acetyl indole,

2 methyl 3 N,N-dimethylaminomethyl 4 di(benzyloxyethyl) amino indole,

2-m-ethyl 3 N,N-dimethylaminomethyl 5 di(benzyloxypropylyamino indole,

2-methyl 3 N,N-dimethylaminomethyl 4 (1'-pyrrolidino) 5 methyl indole,

2-methyl-3-N,N dimethylaminomethyl 5 (1' pyrrolidino) indole,

2-propyl 3 N,N-dimethylaminomethyl 4 (4'-methyl- 1'-piperaziny1) indole,

2-propyl 3 N,N-dimethylaminomethyl-S-(4-methyl-1'- piperazinyl) indole,

3-N,N-dimethylaminomethyl 4 (4' morpholinyl) indole,

Z-methyl 3 N,Ndimethylaminomethyl (4- morpholinyl) indole,

2-methyl-3-N,N-dimethylaminomethyl-4-cyano- 5 methoxy indole,

Z-methyl-3-N,N-dimethylaminomethyl-4-methyl- S-cyano indole,

2-methyl-3-3-N,N-dimethylaminomethyl-4-trifluoromethyl 5 methoxy indole 2-methyl-3-N,N-dimethylaminomethyl-5-trifluoromethyl indole,

Z-rnethyl-3-N,N-dimethylaminomethyl-4-chloro- S-methoxy indole,

3-N,N-dimethylarninomethyl 4 methyl 5 chloro indole,

3-N,N-dimethylaminomethyl 4 bromo indole 2-propyl 3 N,N-dimethylaminomethyl 5 bromo indole,

Z-methyl 3 N,N-dimethylaminomethyl-- 4 fiuoro indole,

Z-methyl 3 N,N-dimethylarninomethyl 5 fluoro indole,

2 methyl 3 N,N-dimethylaminomethyl 4 dimethylsulfamyl indole,

3-N,N dimethylaminomethyl 5 dimethylsulfamyl indole,

2 methyl 3 N,N-dimethylaminomethyl 4 benzylthio 5 methoxy indole, I

2-methyl 3 N,N-dimethylaminomethyl 4 methyl-5- benzylthio indole,

2-methyl 3 N,N dimethylaminomethyl 7 chloro indole,

3-N,N-dimethylaminomethyl-7-chloro indole,

3-N,N-dimethylaminomethyl 7 methyl indole,

3-N,N-dimethylaminomethyl 6 fluoro indole,

2-methyl 3 N,N-dimethylaminomethyl 5 benzylthio indole,

2-methyl 3 N,N-dimethylaminomethyl 4 benzyloxy- S-methyl indole,

2-methyl 3 N,N-dimethylaminomethyl 5 benzyloxy indole,

2-methyl 3 N,N-dimethylaminomethyl 4 p ethylbenzyloxy indole,

2-methyl-3-.N,N dim-ethylaminomethyl 5 p ethylbenzyloxy indole,

2-methyl 3 N,N-dimethylaminomethyl 4 p-bromobenzyloxy 5 methyl indole,

2-methyl 3. N,N-dimethylaminomethyl 5 p-chlorobenzyloxy indole,

3-N,N-dimethylarninomethyl 4 allyl indole,

3-N,N-dimethylaminomethyl 5 allyl indole,

3-N,N-dimethylaminomethyl 4 (prop 2' enoxy)-5 methoxy indole,

2-methyl 3 N,N-dimethylaminomethyl 5 (prop-2'- enoxy) indole,

2-methyl 3 N,N-dimethyl-aminomethyl 4 (1'-azacyclopropyl) indole,

3-N,N-dimethylaminomethyl 5 (1' azacyclopropyl) indole,

3-N,N-dimethylaminomethyl 4 cyclopropylmethoxymethyloxy indole, I

3-N,N-dim-ethylaminomethyl 5 cyclopropylmethoxymethyloxy indole,

2-methyl 3 N,N-dimethylarninomethyl 4 cyclobutylethoxymethyloxy 5 methyl indole,

2-methy1 3 N,N-dimethylaminomethyl 4 methyl-5- cyclobutylethoxymethyloxy indole,

2-methyl 3 N,N-dimethylaminomethyl 4 dimethylsulfarnyl 5 methoxy indole,

Z-methyl 3 N,N- dimethylaminomethyl 5 dimethylsulfamyl indole,

2-methyl 3 N,N-dimethylaminomethyl 4,5 methylenedioxy indole,

Z-methyl 3 N,N-dimethylaminomethyl 5,6 methylenedioxy indole,

2-methyl 3 N,N-dimethylaminomethyl 5,6 diethoxy indole,

Z-methyl 3 N,N-dimethylaminomethyl 5,6 dichloro indole,

2-methyl 3 N,N dimethylam-inomethyl 5 dimethylamino indole,

and

2-methyl 3 N,N-dimethylaminomethyl 4,5,6- tribenzoyloxy indole respectively.

EXAMPLE 2 1-p-chlorobenzoyl-Z-methyl-S-methoxy indole A solution of 0.021 mole of 2-methy1 5 methoxy indole in 20 m1. of dimethylformamide is added dropwise to a cold suspension of 1.0 gram (0.22 mole) of sodium hydride (52% dispersion in mineral oil) and 25ml. of dirnethylformamide. The mixture is stirred at room temperature for 20 minutes, cooled, and treated with (0.0222 mole) p-chlorobenzoyl chloride. The reaction mixture is stirred at room temperature for about 16 hours and poured into 260 ml. of ice water. The aqueous mixture is extracted with three 250 ml. portions of ether. The ether extract is washed with ml. of potassium bicarbonate solution and three 100 ml. portions of Water. The ether layer is dried and concentrated at reduced pressure to give 1-p-chlorobenzoyl-Z-methyl 5 methoxy indole.

Similarly, when using 3,4,5-trimethoxybenzoyl chloride, p-trifluoroacetylbenzoyl chloride, p-N,N-dimethylsulfamylbenzoyl chloride, p-difluoroacetylbenzoic acid, p-carbomethoxybenzoyl chloride, p-formylbenzoyl chloride, p-trifluoromethylthiobenzoyl chloride, I N,N-dimethyl-p-sulfonamidobenzoyl chloride, p-methylsulfinylbenzoyl chloride, p-methylsulfonylbenzoyl chloride, p-benzylthiobenzoyl chloride,

2-thenoyl chloride,

3-thenoyl chloride,

4-thiazole carbonyl chloride, 5-chloro-2-furoyl chloride, 5-methyl-4-oxazole carbonyl chloride, p-nitrophenyl nicotinate, p-dimethylaminobenzoyl chloride, p-acetaminobenzoyl chloride, o-fluoro-p-chlorobenzoyl chloride, o-methoxy-p-chlorobenzoyl chloride, and 2,4,5-trichlorobenzoyl chloride in place of p-chlorobenzoyl chloride in the above example, there are obtained 1-3,4,5trimethoxybenzoyl-Z-methyl-S-methoxy indole, 1-p-trifluoroacetylbenzoyl-2-methyl-S-methoxy indole, 1-p-N,N-dimethylsulfamylbenzoyl-2-rnethyl-5-methoxy indole, 1p-difluoroacetylbenzoyl-2-methy1-5-methoxy indole, 1-p-carbomethoxybenzoyl-2-methyl-5-methoxy indole, 1-p-formylbenzoyl-Z-methyl-S-methoxy indole, l-p-trifluoromethylthiobenzoyl-Z-methyLS-methoxy indole, 1-N,N-dimethyl-p-sulfonamidobenzoyl-2-methy1-5- methoxy indole, 1-p-methylsulfinylbenzoyl-2-methyl-5-methoxy indole, 1-p-methylsulfonylbenzoyl-Z-methyl-S-methoxy indole, 1-pbenzylthiobenzoyl-Z-methyl-5-methoxy indole, 1-2-thenoyl-2-methyl-S-methoxy indole, 1-3-thenoyl-2-methyl-5-methoxy indole, 1-4-thiazole carbonyl-Z-methyl-5-methoxy indole, 1-5-chloro-2-furoyl-2-methyl-S-methoxy indole, 1-5 -methyl-4-oxazole carbonyl-2-methyl-5-methoxy indole, 1-nicotinoyl-2-methyl-5-rnethoxy indole, 1-p-dimethylaminobenzoyl-Z-methyl-S-methoxy indole, 1-p-acetaminobenzoyl-Z-methyl-S-methoxy indole, 1-o-fluoro-p-chlorobenzoyl-Z-methyI-S-methoxy indole,

2-methyl-3-formy1-4-p-bromobenzyloxy-S-methyl indole, 2-methyl-3-formy1-S-p-chlorobenzyloxy indole, 3-formyl-4-ally1 indole, 3-formyl-5-allyl indole, 3-for1ny1-4-( prop-2'-enoxy)-5 -methoxy indole, Z-methyl-S-formyl-S-(prop-2-enoxy) indole, 2-rnethyl-3-f0rmyl-4-(1'-azacyclopropyl) indole, 3-formyl-5-(1'-azacyclopropyl) indole, 3-formy1-4-cyclopropylmethoxymethyloxy indole, 3-formy1-5-cyclopropylmethoxymethyloxy indole, 2-methy1-3-formyl-4-cyclobutylethoxymethyloxy-S-methyl indole, 2-methyl-3-formyl-4-methyl-5-cyclobutylethoxymethyloxy indole, 2-methyl-3-formyl 4-dimethylsu1famyl-5-methoxy indole, 2-methy1-3-formyl-S-dimethylsulfamyl indole, Z-methyl-3-formyl-4,S-methylenedioxy indole, 2-methyl-3-formyl-5,6-methylenedioxy indole, 2-rnethyl-3-forrnyl-5,6-diethoxy indole, 2-methyl-3-formyl-5,6-dichloro indole, 2-methy1-3-formyl-5-dimethylamino indole, and Z-methyl- 3-formy1-4,5,6-tribenzy1oxy indole respectively.

EXAMPLE 4 2-methyl-3-acetyl-5-methyl indole To a Solution of 200 ml. of acetic anhydride and 10.8 grams of sodium acetate is added 28 grams of 2-methyl- S-methyl indole. The solution is refluxed for 6 hours and then concentrated in vacuo to a small volume. The mixture is then triturated in ice water and extracted with (3X 150 ml.) ether. The ethereal solution is washed with sodium bicarbonate, water, and dried over sodium sulfate. The solution is then filtered and concentrated to yield 2-methyl-3-acetyl-5-methyl indole.

When chlor-o acetic anhydride, butanoic anhydride, fl-methoxy propionic anhydride, B-benzyloxy propionic anhydride, B-propenoic anhydride, benzoic anhydride, and 'y-butynoic anhydride are used in place of acetic anhydride in the above example, there are obtained the corresponding 2-methyl-3-acyl-5-methyl indoles.

Similarly, when 2-methy1 4-methyl S-methyl indole, 2-methyl 7-methy1 indole, 2-(prop-2-en)-4-benzyloxy indole, 2 methyl 5 benzyloxy indole, 2 methyl-4- ethoxy S-methoxy indole, 2-methyl-4-nitro-S-methoxy indole, 2-methyl S-nitro indole, 2-methyl-4-benzylideneamino S-ethoxy indole, 2 methyl S-benzylideneamino indole, 4-benzylidenearninoethyl S-methoxy indole, 2- methyl S-benzylideneaminoethyl indole, 2-methy1 4-di (ethy1)amin0 indole, Z-methyl 5 di(propyl)amino indole, 2-rnethyl 4-acetamido 5-propoxy indole, 2-n1ethyl- S-acetamido indole, 4-acetyl S-methyl indole, 2-methyl- 4-p-methoxyphenyl 5 acetyl indole, 2-methyl-4-di(benzyloxyethyDamino indole, 2 methyl 5-di( benzyloxypropyl)amino indole, 2-methy1 4 (1'-pyrrolidino)-5- methyl indole, 2-methyl 5-(1'-pyrrolidino) indole, 2- propyl 4-(4' methyl-1-piperazinyl) indole, 2-propyl- 5-(4' methyl l'-piperazinyl) indole, 4 (4-morpholinyl) indole, 2-methyl 5-(4'-morpholiny1) indole, 2- methyl 4-cyano S-methoxy indole, 2-methyl 4-methyl- S-cyano indole, 2-methyl 4-trifluoromethyl S-methoxy indole, 2-methyl S-trifluoromethyl indole, 2 methyl- 4-chloro 5-methoxy indole, 4-methyl S-chloro indole, 4-bromo indole, 2 propyl-5 bromo indole, 2-methyl- 4-flu0ro indole, 2 methyl-S-fiuoro indole, 2 methyl-4- dimethylsulfamyl indole, 5 dimethylsulfamyl indole, 2- methy1-4-benZylthio-5 methoxy indole, 2 methyl 4- rnethyl S-benzylthio indole, Z-methyl 7-ch1oro indole, 7-chloro indole, 7 methyl indole, 6-fluoro indole, 2- methyl S-benzylthio indole, 2 methyl-4 benzyloxy- S-methyl indole, 2 methyl 5-benzyloxy indole, Z-methyl- 4-p ethylbenzyloxy indole, 2 methyl-S-p ethylbenzyloxy indole, 2-methyl 4-p-brom0benzyloxy S-methyl indole, 2-methyl 5-p-chlorobenzyloxy indole, 4 allyl indole, S-allyl indole, 4 (prp-2' enoxy) S-methoxy indole, Z-methyl S-(prop 2'-enoxy) indole, 2 -methyl 4-( 1'-azacyc1opropyl) indole, (1-azacyclopropyl) indole, 4-cyclopropylmethoxymethyloxy indole, 5 cyclopropylmethoxymethyloxy indole, 2 methyl-4 cyclobutylethoxymethyloxy S-methyl indole, 2 methyl-4- methyl 5 cyclob-utylethoxymethyloxy indole, 2-methyl- 4 dimethylsulfamyl S-methoxy indole, 2 methyl-5- dimethyl sulfamyl indole, 2 methyl 4,5 methylenedioxy indole, 2 methyl 5,6-methylenedioxy indole, 2-methyl 5,6-diethoxy indole, 2 methyl-5,6-dichloro indole, Z-methyl S-dimethylamino indole, and Z-methyl- 4,5,6-tribenzyloxy indole are used in place of Z-methyl- S-methoxy indole in the above example, there are obtained 2-methyl 3-acety1-4 methyl-5 methyl indole, 2-methyl 3-acetyl-7 methyl indole, 2-(prop 2-en)- 3-acety1 4-benzyloxy indole, 2-methyl 3-acetyl 5- benzyloxy indole, 2-methyl 3-acetyl-4-ethoxy-5-methoxy indole, 2-methyl 3-acetyl-4-nitro S-methoxy indole, 2-methyl 3-acetyl S-nitro indole, Z-methyl 3-acetyl- 4-benzylideneamino S-ethoxy indole, Z-methyl 3-acetyl- 5 benzylideneamino indole, 3 acetyl-4 benzylideneaminoethyl S-methoxy indole, 2-methyl 3-acetyl-5-benzylideneaminoethyl indole, 2 methyl-3 acetyl-4 di (ethyDamino indole, 2 methyl-3 acetyl-S di(propyl) amino indole, 2-methyl 3-acetyl-4 acetamido-S propoxy indole, 2-methyl 3-acetyl-5 acetamido indole, 3-acety1 4-acetyl-5 methyl indole, Z-methyl 3-acetyl- 4-p methoxyphenyl S-aeetyl indole, 2-methyl 3-acetyl- 4-di( benzyloxyethyl) amino indole, 2 methyl-3 acetyl- 5 di(benzyloxypropyl) amino indole, 2-methyl-3-acetyl- 4-(1' pyrrolidino S-methyl indole, Z-methyl 3-acetyl- 5 (1-pyrrolidino) indole, 2 propyl-3 acetyl-4 (4- methyl 1' piperazinyl)indole, 2 propyl 3 acetyl- 5-(4-methyl 1-piperazinyl) indole, 3-acetyl 4-(4'- morpholinyl) indole, Z-methyl 3-acetyl 5-(4'-morpholinyl) indole, 2-methyl 3-acetyl 4-cyano S-methoxy indole, 2-methy1 3-acetyl- 4 methyl-S-cyano indole, Z-methyl 3-acetyl-4 trifluoromethyl S-methoxy indole, 2-methy1 3-acetyl-5 trifluoromethyl indole, 2- methyl 3-acetyl-4 chloro-S methoxy indole, 3-acetyl- 4-methyl S-chloro indole, 3-acetyl 4-bromo indole, 2- propyl 3-acetyl-5 bromo indole, Z-methyl 3-acetyl- 4-fluoro indole, 2-methyl 3-acetyl S-fluoro indole, 2- methyl 3-acetyl-4 dimethylsulfamyl indole, 3-acetyl- S-dimethylsulfamyl indole, 2-methy1 3-acetyl-4 benzylthio-S-methoxy indole, 2 methyl-3 acetyl-4-methyl- S-benzylthio indole, Z-methyl 3-acetyl-7 chloro indole, 3-acetyl 7-chloro indole, 3-acetyl 7-methyl indole, 3-acety1 6-fluor0 indole, 2-methyl 3-acetyl-5-benzylthio indole, 2-methyl 3-acetyl 4-benzyloxy S-methyl indole, 2-methyl-3 acetyl-S benzyloxy indole, 2-methyl- 3-acetyl 4-p-ethylbenzyloxy indole, 2 methyl-3 acetyl- S-p-ethylbenzyloxy indole, 2-methyl 3-acetyl 4 pbromobenzyloxy S-methyl indole, Z-methyl 3-acetyl- S-p-chlorobenzyloxy indole, S-acetyl 4-allyl indole, 3- acetyl S-allyl indole, 3-acetyl 4-(pr0p 2'-enoxy) 5- methoxy indole, 2-methyl 3-acetyl S-(prop 2-enoxy) indole, 2-methy1 3-acetyl-4 (1'-azacyclopropyl) indole, 3-acety1 5-(1-azacyclopropyl )indole, 3 acetyl- 4-cyclopropylmethoxymethyloxy indole, 3 acetyl 5- cyclopropylmethoxymethyloxy indole, Z-rnethyl 3-acetyl- 4 cyclobutylethoxymethyloxy-S-methyl indole, 2-methyl- 3- acetyl 4-methy1 5-cyclobuty1ethoxymethyloxy indole, Z-methyl 3-acetyl 4-dimethylsulfamyl-5-methoxy indole, 2 methyl 3 acetyl S-dimethylsulfazmyl indole, 2-methyl-3 acetyl 4,5-methylenedioxy indole, Z-methyl- 3-acetyl 5,6 methylenedioxy indole, 2-methyl 3-acety1- 5,6-diethoxy indole, 2-methyl 3-acetyl 5,6-dichloro indole, Z-methyl 3-acetyl S-dimethylamino indole, and 2-methyl 3-acetyl 4,5,6-tribenzyloxy indole respectively. In those cases where anhydrides or acid chloride cannot be used as solvents also, dimethoxythane is used.

EXAMPLE 5 2-methyl-3-ethylirninomethyl-5-methoxy indole A mixture of 0.02 mole of 2-methyl-3-aldehyde 5- methoxy indole and 250 ml. of ethylamine is stirred at room temperature for 1 hour. The solution is then con- 29 centrated in vacuo to yield crude 2-methyl-3-ethyl-iminomethyl-S-methoxy indole.

When the 3-aldehyde substituted indoles obtained from Example 3 and the 3-keto substituted indoles obtained from Example 4 are used in place of 2-methyl-3-aldehyde-S-methoxy indole in the above example, there are obtained the corresponding 3-ethyliminom-ethyl indoles and 3-ethyl-imino substituted methyl indoles respectively.

Similarly, when methylamine, 3-fluoropropylamine, 3- hydroxypropylamine, prop Z-en-amine, but-3-yn-amine, methoxyethylamine, benzylethylamine, cyclopropylmethyl-amine, cyclohexylamine, tetrahydrofurfurylamine, and cyclobutylmethylamine are used in place of ethylamine in the above example, there are obtained the corresponding 3-substituted-iminomethyl indoles.

EXAMPLE 6 2-methyl-3-ethylaminomethyl-S-methoxy indole 0.1 gram of palladium on alumina is added to a solution of 0.01 mole of 2-methyl-3-ethyliminomethyl-5- methoxy indole in 200 ml. of methanol and the solution reduced at room temperature under an. atmosphere of hydrogen. The solution is then filtered and the filtrate evaporated to dryness to yield crude 2-methyl-3-ethylaminomethyl-S-methoxy indole.

When the 3 ethyliminomethyl substituted indoles, 2- methyl 3-substitutediminomethyl 5-methoxy indoles, and 3-imino substitutedmethyl indoles obtained from Example 5 are used in place of 2-methyl-3-ethyliminomethyl-S-methoxy indole in the above example, there are obtained the corresponding 3-aminomethyl substituted indoles, 3-(amino substitutedmethyl) indoles, and 2-methyl-3-substitutedaminomethyl S-methoxy indoles respectively. (Those compounds containing groups which are affected by the above reduction are not used ormust be protected. Examples of such groups are cyano, nitro, alkenyl, and the like. However, in those cases where a dibenzylamino group and benzyloxy group are present and the respective amino or hydroxy group is desired, this reduction step will convert those groups to the desired groups.)

EXAMPLE 7 2-methyl-3-benzylideneaminomethyl-S-methoxy indole A solution of 0.02 mole of 2-methyl-3-aminomethyl-5- methoxy indole and 0.02 mole of benzaldehyde in 200 ml. of benzene is refluxed for 1 hour. The benzene solution is then distilled until water no longer comes 01f. At this point, the solution is concentrated in vacuo. The concentrate is then filtered and the cake Washed with cold (2X 25 ml.) ethanol. The cake is then dried in vacuo to yield 2-methyl- 3-benzylideneaminomethyl-S-methoXy indole;

When the 3-aminomethyl substituted indoles obtained from Example '6 are used in place of the 2-methyl-3-aminomethyl-S-methoxy indole in the above example, there are obtained the corresponding 3-benzylideneaminomethyl substituted indoles. i

' EXAMPLE 8 2-methyl-3-N,N-diethylaminomthyl-S-methoxy indole A mixture of 0.01 mole of 2-methyl-3-aminomethyl-5- methoxy indole, 0.022 mole of ethyl iodide and 0.015 mole of sodium bicarbonate in 50 ml. of anhydrous 1,2-dimethoxyethane is stirred at room temperature under nitrogen for 8 hours. The mixture is then filtered and the solvent removed in vacuo. The residue thus obtained is chromatographed on 150 grams of a neutral alumina column and eluted with ether-petroleum ether (v./v. 20100%) to obtain 2-methyl-3-N,N-diethylaminomethyl 5 methoxy indole.

When the (3-aminomethyl) substituted indoles, 3-(amino-substituted methyl) indoles, and 2-methyl-3-substituted aminomethyl-S-methoxy indoles obtained from Example 6 are used in place of 2-methyl-3-N,N-diethylaminomethyl- S-methoxy indole in the above example, there are obtained the corresponding N,N-diethylamino substituted indoles, diethylamino-substituted methyl indoles, and 2-methyl-3- ethyl-substituted aminomethyl-S-methoxy indoles.

Similarly, when 1-iodo-3-chloropropane, 3-benzyloxypropyl bromide, 3-br0mopropanol, allyl bromide, l-bromide-prop-3-yne, 3-methoxypropyl bromide, cyclopropylmethyl bromide, cyclobutylmethyl bromide, 1,5-diiodopentane, dibromodiethyl ether, di(B-chloroethyl)methylamine-HCl, di([3-chloroethyl)amine-HCI, diQS-chloroethyl)anilin'e-HC1, 1,4-dichlorobutane, and diQS-chloroethyl) fi-hydroxyethylamine-HCI are used in place of the ethyl iodide in the above example, there are obtained the corresponding 2-methyl-3-N-substituted aminomethyl 5 methoxy indoles and 2-methyl-3-N-cyclic-aminomethyl-5-methoxy indoles.

EXAMPLE 9 1-p-chlorobenzoyl-2-methyl-3-N-ethyliminomethyl5- methoxy indole A solution of 0.21 mole of 2-methyl-3-N-ethyliminomethyl-S-methoxy indole in 30 ml. of dimethylformamide is added to a suspension of 0.22 mole of sodium hydride in 35 ml. of dimethylformamide. After stirring the reaction at room temperature for /2 hour, the mixture is cooled and treated with 0.22 mole of p-chlorobenzoyl chloride. The mixture is stirred at room temperature for 12 hours and subsequently poured into 250 ml. of ice water. The mixture is then extracted with (2x 200 ml.) ether. The combined ether extract is washed with a dilute aqueous solution of potassium bicarbonate followed by (3x ml.) water. The ether layer is dried over sodium sulfate and concentrated in vacuo to give 1-p-chlorobenzoyl-Z-methyl- 3-N-ethyliminomethyl-5-methoxy indole.

When the acylating agents obtained from Example 2 are used in place of p-chlorobenzoyl chloride in the above example, there are obtained the corresponding 1-acyl-2- methyl-3-N-ethyliminomethyl-5-methoxy indoles.

Similarly, when the 3-ethyliminomethyl indoles, 3-ethylimino substituted methyl indoles, and the 3-N-substituted iminomethyl indoles obtained from Example 5 are used in place of 2-methyl-3-N-ethyliminomethyl-S-methoxy indole in the above example, there are obtained the corresponding 1-p-chlorobenzoyl-3-N-ethyliminomethyl indoles, 1-p-chlorobenzoyl-3-N-ethylimino substituted methyl indoles, and 1-p-chlorObenzoyl-3-N-substituted iminomethyl indoles respectively.

(Those compounds which contain groups which are affected by the above acylation are not used or must be protected prior to acylation. Examples of such groups are those containing active hydrogens, amino, carboxyl, and the like.)

. EXAMPLE 10 2-methyl-3-(2'-methyl-2'-nitrovinyl)-5-methoxy indole A solution of 0.05 mole of 2-methyl-3-aldehyde-5-methoxy indole, 0.01 mole of ammonium acetate, and 250 ml. of nitroethane is stirred for 1 hour at 100 C. The reaction mixture is then cooled and 300 ml. of water are added. The 2-methyl-3-(2'-methyl-2'-n.itrovinyl) 5 methoxy indole which crystallizes out is filtered off and washed with (3X 100 ml.) water. The indole is then recrystallized from chloroformethanol.

When the 3-aldehyde substituted indoles obtained from Example 3 are used in place of 2-methyl-3-aldehyde-5- methoxy indole in the above example, there are obtained the corresponding 3-(2'-methyl-2-nitrovinyl) substituted indoles.

Similarly, when nitromethane, l-nitropropane, 3-chloro l-nitropropane, 2-methoxynitroethane, phenyl-methoxynitromethane, 2-hydroxypropylnitromethane, phenylnitromethane, and 2-benzyloxypropylnitromethane are used in place of nitroethane in the above example, there are obtained the corresponding 2-methyl-3-(2-substituted-2'- nitrovinyD-S-rnethoxy indoles.

Similarly, when the 3-keto substituted indoles obtained EXAMPLE 1 1 u-Methyl- Z-methyl-S -rnethoxy-3 -indolyl) -aminoethane A solution of 2-methyl-3-(2'-methyl-2-nitrovinyl)-5- methoxy indole in 150 ml. oftetrahydrofuran is added dropwise over a period of 15 minutes to a solution heated to 50 C. of 0.03 mole of lithium aluminum hydride in 250 ml. of tetrahydrofuran and the mixture stirred for 10 hours at 50 C. The solution is cooled in an ice bath and then treated with 250 ml. of methanol and 100 ml. of, saturated aqueous sodium sulfate. The mixture is then filtered, washed with chloroform, and then evaporated to dryness. The resultant residue is distributed between.

ether and aqueous tartaric acid solution. The acid solution is then adjusted to alkalinity with dilute aqueous sodium hydroxide while cooling with ice. The solution is then quickly shaken with ether (2X 100 ml.) and the combined ether extracts are dried over sodium sulfate and the ether evaporated off to yield a-methyI-(Z- methyl-S- methoxy-3-indolyl) -aminoethane.

When the 3-(2'-methyl-2'-nitrovinyl) substituted indoles, 2-methyl-3- 2'-substituted-2-nitrovinyl) -5-methoxy indoles, and 3-(1'-substituted-2-methyl-2-nitrovinyl) substituted indoles obtained from Example are used in lace of 2-methyl-3-(2-methyl-2'-nitrovinyl)-5-methoxy indole in the above example, there are obtained the corresponding u-methyl-3-(aminoethyl) substituted indoles, a-substituted (2-methyl-5 methoxy-3-indolyl) aminoethane, and a,5-disubstituted (substituted 3-indolyl)- aminoethanes respectively. 1

(Those compounds containing groups which will be affected by the above reduction must be removed or protected prior to the reduction. Such groups are nitro, cyano, alkenyl, and the like.)

EXAMPLE 12 1-p-chlorobenzoyl-2-methyl-3-(2'-methyl-2'-nitrovinyl)- S-methoxy indole A solution of 0.03 mole of Z-methyl-3-(2'-methyl-2- nitrovinyl)-S-methoxy indole in ml. of dimethylformamide is added dropwise to a cold suspension of 0.33 mole of sodium hydride and ml. of dimethylformamide. \After the mixture is stirred at room temperature for 30 minutes, 0.33 mole of p-chlorobenzoyl chloride is added. The reaction mixture is then stirred at room temperature for 12 hours and the mixture subsequently poured into 300 ml. of ice water. The aqueous mixture is then extracted with (2X 300 ml.) ether. The combined ether extract is then washed with 75 m1. of aqueous potassium bicarbonate, followed by 2 X 125 ml. portions of water. The ether layer is then dried over sodium sulfate and concentrated in vacuo to yield 1 p chlorobenzoyl 2 methyl 3 (2- methyl-Z-nitrovinyl)-5-methoxy indole.

When the corresponding 3-(2methyl-2'-nitrovinyl) substituted indoles, 3-(1'-substituted-2-methyl-2-nitrovinyl) substituted indoles, and 2-methyl-3-(2'-substituted- 2-nitrovinyl)-5-methoxy indoles are used in place of 2- Inethyl-3-(2-methyl-2'-nitrovinyl)-5-methoxy indole in the above example, there are obtained the corresponding 1- p-chlorobenzoyl-3-(2-methyl-2-nitrovinyl) substituted indoles, 1 p chlorobenzoyl-3-(1-substituted-2'-n1ethyl-2fnitrovinyl) substituted indoles, and 1-p chlorobenzoyl-2- methyl-3-(2'-substituted-2-nitrovinyl)-5-rnethoxy indoles respectively.

Similarly, when the acylating agents obtained from Example 2 are used in place of the p-chlorobenzoyl chloride in the above example, there are obtained the correspondin g 1-acyl-2-methyl-3-(2-methyl-2'-nitrovinyl)-5-methoxy indoles.

(Those compounds which contain groups which will be 32 affected by the above acylation are either protected or removed prior to acylation. Such groups are those containing an active hydrogen such as amino, carboxyl, and the like.)

EXAMPLE 13 u-Methyl- (Z-methyl-S-methoxy- 3 -indolyl) -N-ethylaminoethane A mixture of 0.10 mole of a-methyl-(Z-methyI-S-methoxy-3-indolyl)-aminoethane, 0.11 mole of ethyl iodide, 1

and 0.15 mole of sodium bicarbonate in 50 ml. of anhydrous 1,2-di-1nethoxyethane is heated on a steam bath under nitrogen for 3 hours. The mixture is then filtered andthe solvent removed in vacuo. The residue thus obtained is chromatographed on 250 grams of a neutral alumina column and eluted with ether-petroleum ether (v./v. 50100%,) to obtain a-methyl-(2-methyl-5-me thoxy-3 -indolyl) -N'-ethylarninoethane.

Similarly, when a-methyl-S-(aminoethyl) substituted indoles, a-substituted-(Z-methyI 5 methoxy-3-indoly1)- aminoethanes, and u,j8-disubstituted(substituted-3-indolyl)-aminoethanes obtainedv from Example 11 are used in place of u-methyl-(2-rnethyl-5-methoxy-3-indolyl)- aminoethane in the above example, there are obtained the corresponding a-methyl-3-(N-ethylarninoethyl) substituted indoles, tit-substituted-(Z-methyl-S-methoxy-3-indolyl)-N-ethylaminoethane, and u,fl-disubstituted-(substituted-B-indolyl)-N-ethylaminoethanes respectively.

Similarly, when p-methoxybenzyl chloride, benzyloxyethyl iodide, 3-methoxypropyl iodide, p-methoxyphenylpropyliodide, acetyl iodide, cyclopropylmethyl bromide, cyclobutylmethyl bromide, tetrahydrofurfuryl iodide, cyclohexyl iodide, 1,5-diiodopentane, dibromodiethyl ether, di(/3-chloroethyl)-methylamine hydrochloride, di-(B-chloroethyl)-amine hydrochloride, di-(B-chloroethyl)-aniline hydrochloride, 1,4-dichlorobutane, and di-(B-chloroethyh- ,B-hydroxyethylamine hydrochloride are used in place of ethyl iodide in the above example, there are obtained the corresponding a-methyl-'(2-methyl-5-methoxy-3-indolyl)- N-substituted aminoethanes and a-methyl-(Z-methyI-S- methoxy-3-indolyl)-N,N-cyclicaminoethanes respectively.

EXAMPLE 14 oc-Methyl-2-methyl-5-rnethoxy-3-indolyl acetyl chloride A solution of 2.8 grams of u-methyI-Z-methyl-S-methoxy-3-indolyl acetic acid in 50 ml. of dry ether is treated at 0 C. with 2.7 grams of phosphorus pentachloride with stirring under nitrogen. After the reaction has continued for 3 hours, the solution is diluted with petroleum ether to precipitate the acid chloride. The mixture is filtered and the cake washed with (1:10) ether-petroleum ether and dried in vacuo.

When

a-(but-3-yn)-2-methyl-5-acetarnido-3-indolyl acetic acid, a-phenyl-4-acetyl-5-methyl-3-indolyl acetic acid, 2-methy1-4-p-methoxyphenyl-5-acetyl-3-indolyl acetic acid, 2-methyl-4-di( benzyloxyethyl)amino-3-indolyl acetic acid, 2-methyl-5-di(benzyloxypropyl)amino-B-indolyl acetic acid, 2-n1ethyl-4-(1'-pyrr0lidino)-5-methyl-3-indolyl acetic acid, 2-rnethy1-5-(1'-pyrrolidino)-3-indolyl acetic acid, 2-propyl-4-(4'-rnethyl-l'-piperazinyl) -3-indolyl acetic acid, 2-propyl-5-(4'-rnethyl-1-piperazinyl)-3-indolyl acetic acid, 4-(4'morpholinyl)-3-indolyl acetic acid, 2-rnethyl-5-(4-morpholiny1)-3-indolyl acetic acid, 2-rnethyl-4-cyano-5-rnethoxy-3-indolyl acetic acid, 2-rnethyl-4-methyl-5-cyano-3-indolyl acetic acid, Z-methyl-4-trifiuoromethyl-5-rnethoxy-3-indolyl acetic acid, 2-methyl-5-trifluoromethyl-3-indolyl acetic acid, 2-methyl-4-chloro-5-methoxy-3-indolyl acetic acid, 4-methy1-5-chloro-3-indolyl acetic acid, 4-brorno-3-indolyl acetic acid, 2-propyl-S-bromo-3-indolyl acetic acid, 2-methyl-4fl uoro-3-indolyl acetic acid, Z-methyl-5-fiuoro-3-indolyl acetic acid, 2-methy1-4-dimethylsulfarnyl-3-indolyl acetic acid, S-dimethylsulfamyl-3-indolyl acetic acid, 2-methyl-4-benzylthio-S-rnethoxy-3-indolyl acetic acid, 2-methyl-4-methyl-5-benzylthio-3-indolyl acetic acid, 2-Inethyl-7-chloro-3-indolyl acetic acid, 7-chloro-3-indolyl acetic acid, 7-methyl-3-indolyl acetic acid, 6-fluoro-3-indolyl acetic acid, 2-methyl-5-benzylthio-3-indolyl acetic acid, 2-methyl-4-henzyloxy-S-methyl-B-indolyl acetic acid, 2-rnethyl-5-benzyloxy-3-indolyl acetic acid, 2-methyl-4-p-ethylbenzyloxy-3-indolyl acetic acid, 2-rnethyl-5-p-ethylbenzyloxy-3-indolyl acetic acid, 2-methyl-4-p-brornobenzyloxy-5-rnethyl-3-indolyl acetic acid, Z-methyl-S-p-chlorobenzyloXy-3-indolyl acetic acid, 4-allyl3indolyl acetic acid, 5-a1lyl-3-indolyl acetic acid, 4-(prop-2'-enoxy)-5-methoxy-3-indolyl acetic acid, 2-methyl-5-(prop-2-enoxy)-3-indolyl acetic acid, 2-rnethyl-4-(1'-azacyclopropyl)-3-indolyl acetic acid, 5-(1'-azacyclopropyl)-3-indolyl acetic acid, 4-cyclopropylmethoxymethyloxy-3-indolyl acetic acid, 5-cyclopropylmethoxyrnethyloxy-3-indolyl acetic acid, 2-methyl-4-cyclobutylethoxyrnethyloxy-S-rnethyl-3- indolyl acetic acid, 7 Z-methyl-4-rnethyl-S-cyclobutylethoxymethyloxy-3- indolyl acetic acid, 2-methyl-4-dimethylsulfamyl-S-methoxy-3-indolyl acetic acid, Z-methyl-S-dirnethylsulfarny1-3-indolyl acetic acid, 2-methyl-4,S-methylenedioxy-3-indolyl acetic acid, Z-methyl-S,6-methylenedioxy-3-indolyl acetic acid, Z-methyl-S,6-diethoxy-3-indolyl acetic acid, 2-methyl-5,6-dichloro-3-indolyl acetic acid, Z-methyl-5-dirnethylamino-3-indolyl acetic acid, and 2-methyl-4,5,6-tribenzyloxy-3-indolyl acetic acid are used in place of 2-methy1-5-rnethoXy-3-indolyl acetic acid in the above example, there are obtained 2-methyl-4-rnethyl-5-methyl-3-indolyl acetyl chloride, a-ethyl-Z-methyl-7-methyl-3-indolyl acetyl chloride, a-rnethyl-Z-(prop-Z-en)-4-benzyloxy-3-indolyl acetyl chloride, a-chloroethyl-2-methyl-5-benzyloxy-3-indolyl acetyl chloride, u-ethoxy-2-methyl-4-ethoxy-5-methoXy-3-indolyl acetyl chloride, u-brornopropyl-2-rnethyl-4-nitro-5-rnethoxy-3-indolyl acetyl chloride, a-benzyloxy-Z-methyl-S-nitro-3-ir1d0lyl acetyl chloride,

2-methyl-4-benzylideneamino-5-ethoxy-3-indolyl acetyl chloride, Z-InethyI-S-benZyIideneamino-3-indoly1 acetyl chloride, 4-benzylidenearninoethyl-S-methoxy-3-indo1yl acetyl chloride, Z-methyl-S-benzylideneaminoethyl-3-indolyl acetyl chloride, u-benzyloxyethyl-2-methyl-4-di (ethyl amino-3-indolyl acetyl chloride, oc-benzyloxyrnethyl-Z methyl-S-di (propyl) amino-3- indolyl acetyl chloride, a- (prop-2-en) -2-rnethyl-4-acetamido-5-propoXy-3- indolyl acetyl chloride, OL- (but-3-yn) -2-methyl-5-acetamido-3-indolyl acetyl chloride, u-phenyl-4-acetyl-5-methyl-3-indolyl acetyl chloride, 2-rnethyl-4-p-methoxyphenyl-5-acetyl-3-indolyl acetyl chloride, 2-methyl-4-di(benzyloxyethyl)amino-3-indolyl acetyl chloride, Z-methyl-S-di(benzyloxypropyl)amino-3-indolyl acetyl chloride, 2-rnethyl-4-( 1'-pyrrolidino -5-methyl-3-indolyl acetyl chloride, 2methy1-5-( l'-pyrrolidino)-3-indolyl acetyl chloride, 2-propyl-4-(4'-methyl-1'-piperaziny1)-3-indolyl acetyl chloride, 2-propyl-5- (4'-methyll -piperazinyl) -3-indoly1 acetyl chloride, 4-(4-morpholinyl)-3-indolyl acetyl chloride, Z-methyl-S-(4'-morpholinyl)-3-indolyl acetyl chloride, 2-methyl-4--cyano-5-methoXy-3-indolyl acetyl chloride, 2-methyl-4-methyl-5-cyano-3-indolyl acetyl chloride, 2-methyl-4-trifiuorornethyl-5-rnethoxy-3-indolyl acetyl chloride, 2-methyl-5-trifiuorornethyl-3-indolyl acetyl chloride, 2-rnethyl-4-chloro-5-methoXy3-indolyl acetyl chloride, 4-methyl-5-chloro-3-indolyl acetyl chloride, 4-bromo-3-indolyl acetyl chloride, 2-propyl-S-bromo-B-indolyl acetyl chloride, Z-methyl-4-fluoro-3-indolyl acetyl chloride, 2-methyl-5-fluoro-3-indoly1 acetyl chloride, 2-methyl-4-dimethylsulfamyl-3-indolyl acetyl chloride, 5-dimethylsulfamyl-3-indolyl acetyl chloride, 2-methyl-4-benzylthio-S-rnethoxy-S-indolyl acetyl chloride, 2-methyl-4-methyl-5-benZylthio-3-indolyl acetyl chloric'e, 2-rnethyl-7-chloro-3-indolyl acetyl chloride, 7-chloro-3-indolyl acetyl chloride, 7-methyl-3-indolyl acetyl chloride, 6-fiuoro-3-indolyl acetyl chloride, Z-methyl-S-benzylthio-B-indolyl acetyl chloride, 2-methyl-4-benzyloxy-S-rnethyl-3-indolyl acetyl chloride, 2-methyl-5-benzyloxy-3-indolyl acetyl chloride, 2-rnethyl-4-p-ethylbenzyloxy-3-indolyl acetyl chloride, Z-methyl-S-p-ethylbenzyloxy-3-indolyl acetyl chloride, 2-methy1-4-p-brornobenzyloxy-5-methyl-3-indolyl acetyl chloride, 2-methy1-5-p-chlorobenzyloxy-3-indolyl acetyl chloride, 4-allyl-3-indolyl acetyl chloride, 5-allyl-3-indolyl acetyl chloride, 4-(prop-2'-enoxy)-5-methoxy-3-indolyl acetyl chloride, Z-methyl-S-(prop-2-enoxy)-3-indoly1 acetyl chloride, 2-methyl-4( l'-azacyclopropyl)-3-indolyl acetyl chloride, 5-(l-azacyclopropyl)-3-indolyl acetyl chloride, 4-cyclopropylrnethoxyrnethyloxy-3-indolyl acetyl chloride, 5-cyclopropylrnethoxymethyloxy-3-indolyl acetyl chloride, 2-rnethyl-4-cyclobutylethoxymethyloxy-5-methyl-3- indolyl acetyl chloride, 2-rnethyl-4-rnethyl-5 cyclobutylethoxymethyloXy-3- indolyl acetyl chloride, 2-methyl-4-dimethylsulfamyl-5-methoxy-3-indolyl acetyl chloride, Z-methyl-S-dimethylsulfarnyl-3-indolyl acetyl chloride. 2-methyl-4,5-methylenedioXy-3-indolyl acetyl chloride,

35 2-methyl-5,6-methylenedioxy-3-i.ndolyl acetyl chloride, 2-methyl-5,6-diethoxy-3-indolyl acetyl chloride, 2-methyl-5,6-dichloro-3-indolyl acetyl chloride, 2-methy1-5-dimethylamino-3-indolyl acetyl chloride, and 2-methyl-4,5,6-tribenzyloxy-3-indolyl acetyl chloride respectively.

7 EXAMPLE 15 1- 2-methyl-5-methoxy-3-indolyl 1 -methyl butanone To a'solution of 0.05 mole of diethylcadmium in 50 ml. of benzene (prepared according to organic synthesis Coll., volume 3, page 601) is added 0.04 mole of mmethyl-Z-methyl-S-methoxy-3-indolyl acetyl chloride in 15 ml. of benzene with stirring under nitrogen. The mixture is heated at reflux for 1%. hours, cooled, and poured into 1 100 ml. of iced water containing a slight excess of sulfuric acid. The benzene layer is separated and the aqueous layer is extracted With (2X 50 ml.) benzene. The combined extract is washed with water, 5% sodium carbonate, and water successively and dried over sodium sulfate. After evaporation of the solvent in vacuo, the crude prodnet is chromatographed on a column of acid-washed alumina using ether-petroleum ether (v./v. 2050%) as eluent.

When the a-substituted-substituted 3 indolyl acetyl chlorides obtained from Example 14 are used in place of wmethyl-2methyl-S-methoxy-3-indolyl acetyl chloride in the above example, there are obtained the corresponding substituted-1-(3-indolyl) butanones.

Similarly, when di(ethoxyethyl)cadmium, di(benzyloxyethyl)cadmium, di(3 benzyloxypropyl)cadmium, di (prop-2-en)cadmium, diphenylcadmium, and di(but-3-yn) cadmium are used in the above example in place of diethylcadmium, there are obtained the corresponding 2- methyl 5 methoxy 3 indolyl-u-substituted-B-methyl ketones.

(The dibenzyloxyalkyl compounds obtained from above are reduced to the corresponding hydroxyalkyl compounds, which are subsequently converted to the haloalkyl compounds.)

EXAMPLE 16 2-methyl-5-methoxy-3indolyl-a-ethyl-fi-methyl-N- ethyliminoethane A mixture of 0.02 mole of 1-(2-methyl-5-methoxy-3- indolyl)-l-methyl butanone and 250 ml. of ethylamine is stirred at room temperature for 1 hour. The solution is concentrated to dryness to yield crude 2-methyl-5-methoxy-3-indolyl-aethyl-fl-methyl-N-eihyliminoethane.

When the 3-indolyl-u-cthyl-fi-substituted ketones and the 2 methyl-5-methoxy-3-indolyl-a-substituted-p-methyl ketones obtained from Example are used in place of 1-( 2-methyl-5-methoxy-3-indolyl) -1-methyl butanone in the above example, there are obtained the corresponding 3-indolyl-a-ethyl-B-substituted-N-ethyliminoethanes and 2- methyl 5 methoxy-3-indolyl-a-substituted-fi-methyl-N- ethyliminoethanes respectively.

EXAMPLE 17 1-p-chlorobenZoyl-2-methyl-5-methoxy-3-indolyl a-ethylfi-methyl-N-diethyliminoethane A solution of 0.021 mole of 2-methyl-5-methoxy-3- indolyl-a-ethyl-fi-methyl-N-diethyliminoethane in 20 ml. of dimethylformamide is added dropwise to a cold suspension of 1.0 gram (0.022 mole) of sodium hydride (52% dispersion in mineral oil) and ml. of dimethylformamide. The mixture is stirred at room temperature for 20 minutes, cooled, and treated With (0.0222 mole) of pchlorobenzoyl chloride. The reaction mixture is stirred at room temperature for about 16 hours and poured into 260 ml. of ice water. The aqueous mixture is extracted with three 250 ml. portions of ether. The ether extract is washed with 100 m1. of potassium bicarbonate solution and three 100 ml. portions of water. The ether layer is dried and concentrated at reduced pressure to give l-p- 36 chlorobenzoyl 2 methyl-5-methoxy-3-indolylx-ethy1-,B- methyl-N-diethyliminoethane.

When the acylating agents obtained from Example 2 are used in place of p-chlorobenzoyl chloride in the above example, there are obtained the corresponding 1-acyl'2- methyl 5-methoxy-3-indolyl-u-ethyl-fi-methyl-N-diethyliminoethanes.

Similarly, when the substituted 3 indolyl-a-ethyl-B- methyl-N-diethyliminoethanes and the 2-methyl-5 methoxy-3-indolyl-z,fi-substituted-N-diethyliminocthanes obtained from Example 16 are used in place of 2-methyl-5- methoxy 3 indolyl 0c ethyL/i-methyl-N-diethyliminoethane in the above example, there are obtained the corresponding '1 p-chlorobenzoyl-substituted-3-indolyl-u,5- disubstituted-N-disubstituted-iminoethanes.

(Those compounds which contain groups which are affected by the acylation' are either protected or removed prior to acylation. Such compounds are those with groups containing an active hydrogen. Such groups are amino, carboxyl, and the like. This is accomplished by using a benzylalkylamino or dibenzylamino substituent on the ring and after acylation, reducing these groups to obtain the corresponding alky-lamino or amino group. The amino group may be converted to the hydroxy group, which may then be converted to the halogeno group by known means.)

EXAMPLE -18 2-methyl-5-methoxy-3-indolyl-u-methyl-,B-methylethyl alcohol To a solution of 0.05 mole of 3-(2-methyl-5-methoxy- 3-indolyl) butanone in ml. isopropanol is added dropwise a solution of 0.02 mole sodium borohydride in 20 ml. isopropanol with stirring at 0-5 C. After 2 hours the mixture is poured into iced water and extracted with ether. The ethereal solution is washed with 0.1 N hydrochloric acid, saturated sodium bicarbonate and dried over sodium sulfate. The solution is filtered, concentrated and chromatographed on a column of silical gel using ether-petroleum ether -(v./v. 30l00%) as eluent to yield 2-methyl- S-methoxy-3-indolyl-a-rnethyl-[i-methylethyl alcohol.

When the substituted-3-indolyl-a-ethyl-,B-substituted ketones and 2-methyl-5-methoxy-3-indolyl-a-substituted-flmethyl ketones obtained from Example 15 are used in place of the 3-(Z-methyI-S-methoxy-3-indolyl) butanone in the above example, there are obtained the substituted- 3-indolyl-a-ethyl-fi-substituted-ethyl alcohols and Z-methyl-S-rnethoxy-S-indolyl 0c substitutedfi methylethyl alcohols respectively.

(Those compounds which contain groups which are affected by the above reduction must be removed..Such groups are cyano, nitro, and the like.)

EXAMPLE 19 2-methyl-5-methoxy-3-indolyl-a-ethyl-fl-methyl ethylbromide To a solution of 0.03 mole of 2-methyl-5-methoxy-3- indolyl-ix-ethyl-B-methyl ethylalc-ohol in 100 ml. of chloroform is added 0.01 mole of phosphorus tribromide and the reaction mixture stirred for 2 hours at room temperature. The solution is poured into iced Water and the chloroform layer is Washed with aqueous sodium bicarbonate, water, and dried over sodium sulfate. The solution is then concentrated in vacuo to yield Z-methyI-S-methoxy- 3-indolyl-a-ethyl-B- methyl ethylbro-mide.

When substituted-3-indolyl-a-ethyl-fl-substituted ethylalcohols and 2-methyl-5-methoxy-3-ind0lyl-a-substitutedfi-methyl ethylalcohols obtained from Example 18 are used in place of 2-methyl-5-methoxy-3-indolyl-a-ethyl-[i-methyl ethylalcohol in the above example, there are obtained the corresponding substituted-3-indolyl a-ethyl-fi-substituted ethylbromides and 2-methyl-5-methoxy 3 indolyl-ix-substituted-fl-methyl ethylbromides respectively.

(In those cases wherein the indole compound contains 37 an active hydrogen, the group must be either protected or, if not, eliminated.) s r EXAMPLE 20 2-methyl-5-methoxy-3-indolyl-ot-ethyl-fl-methyl ethylcyanide.

To asolution of 0.02 mole of 2-methyl-5-methoxy-3- indolyl-a-ethyl-fi-methyl ethylbromide in 100 ml. of dimethylsulfoxide is added 0.04 mole of potassium cyanide and the mixture is heated on a steam bath for 2 hours. The solution is poured into iced water and extracted with (3X 100 ml.) ether. The combined ether extracts are washed with water and dried over sodium sulfate. The ether solution is then concentrated in .vacuo and the residue is chromatographed on acid-washed alumina or silica gel to yield 2-methyl-5-methoxy-3-indolyl-ot-ethyl-,8-methyl ethylcyanide.

When the substituted-3-indolyl a ethyl-fl-substituted ethylbromides and the 2-methyl-5-methoxy-3-indolylasubstituted-fi-methyl ethylbromides obtained from Example 19 are used in .place of 2-methyl-5-methoxy-3-indolyl-u-ethyl-fl-methyl ethylbromide in the above example, there are obtained the corresponding substitute-d-3-indolyla-ethyl-fl-substituted ethylcyanides and 2-methyl-5-methoxy-3-indolyl-a-substituted ,8 methyl ethylcyanides 'repectively.

EXAMPLE 21 2 methyl--methoxy-3-indolyl-oi-ethyl-B-methyl ethylamine-HCI A,

To a solution of 0.02 mole of Z-methyl-S-methoxy-S- indolyl-a-ethyl-fl-methyl ethylcyanide in 100 ml. of ethanol containing 0.04 mole of HCl is added 0.1 gram of platinum oxide and the solution reduced at room temperature under an atmosphere of hydrogen. The reduced solution is then filtered and the filtrate evaporated in vacuo to dryness to yield crude 2-methyl-5-methoxy-3 indolyl-uethyl-fl-methyl ethylamine hydrochloride.

When the substituted-3-indolyl a ethyl-B-substituted ethylcyanides and 2-methyl-5-methoxy 3 indolyl-ot-substituted-fi-methyl ethylcyanides obtained from Example are used in place of 2-methyLS-methoxy-3 -indolyl-aethyLfl-methyl ethylcyanide in the above example, there are obtained the corresponding substituted-3-indolyl-a-ethyl-fi-substituted ethylamines and 2-methyl-5-methoxy-3- indolyl-a-substituted-fl-methyl ethylamines respectively.

(Those groups on the indole compound which are susceptible to this reduction must be eliminated. Such groups may be represented as cyano, nitro, and the like.)

EXAMPLE. 22

2-methyl-5-methox y-3-indolyl-e-ethyl-B-methyl, I I

benzylideneaminoethane A solution of 0.02 mole of 2-methyl-5-methoxy-3-indolyl-a-ethyl-B-methyl aminoethane and 0.02 mole of benzaldehyde in 200 ml. of benzene is refluxed for 1 hour. The benzene solution is then distilled until water no longer comes off. At this point, the solution is concentrated in vacuo. The concentrate is then filtered and'the cakew shed with cold (2X 25 ml.) ethanol. The cake is then dried in vacuo to yield 2-methyl-5-methoxy-3-indoly1-a-ethyl-;3- methyl benzylidenea'minoethane.

When the substituted-3-indolyla-ethyl-fi-substituted ethylamines and 2-methyl-5-methoxy-3-indolyl-a-substituted- B-methyl ethylamines obtained from Example 21 are used in place of the Z-methyl-5-methoxy-3-indolyl-u-ethyl-fimethyl aminoethane in the above example, there are obtained the corresponding substituted-3-indolyl-u-ethyl-B- substituted benzylideneaminoethanes and 2-methyl-5-rnethoxy-3-indolyl a substituted 9 methyl benzylideneaminoethanes respectively.

38 EXAMPLE 23 Z-methyl-S-methoxy-3-indolyl-a-ethyl-p-methyl- N-ethylaminoethane A mixture of 0.02 mole of 2-methyl-5-methoxy-3- indolyl-u-ethyl-fi-methyl ethylamine, 0.03 mole of sodium bicarbonate, and 0.022 mole of ethyl iodide in 50 ml. of anhydrous 1,2-dimethoxyethane is heated on a steam bath under nitrogen for 3 hours. The mixture is then filteredand the filtrate concentrated in vacuo. The residue thus obtained is chromatographed on 300 grams of a neutral alumina column and eluted with ether-petroleum ether (v./v. 20-100%) to obtain 2-methyl-5-methoxy-3- indolyl-a-ethyl-fi-methyl-N-ethylaminoethane.

' When the substituted 3 indolyl-a-ethyl-fi-substituted ethylamines and 2-methyl-5-methoxy-3-indolyl-a-substituted-B-methyl ethylamines obtained from Example 21 are used in place of 2-methyl-5-methoxy-3-indolyl-a-ethyl- {ft-methyl ethylamine in the above example, there are ob tained the corresponding substituted-3-indolyl-a-ethyl-B- snbstituted-N-ethylaminoethanes and Z-methyI-S-methoxy- 3indolyl-a-substituted-B-methyl-N-ethylaminoethanes respectively.

Similarly, when l-iodo-3-chloropropane, 3-benzyloxypropyl bromide, 3-bromopropanol, allyl bromide, l-bromide-prop-3-yne, 3-methoxypropy1 bromide, cyclopropylmethyl bromide, cyclobutylmethyl bromide, 1,5-diiodopentane, dibromodiethyl ether, di(,8-chloroethyl)methylamine -HC1, di B-chloroethyl) amine -HCl, di (fl-chloroethyDaniIine-HCI, 1,4-dichlorobutane, and di(;3-chloroethyl) fi-hydroxyethylamine-HCI are used in place of the ethyl iodide in the above example, there are obtained the corresponding 2 methyl 5-methoxy-3-indolyl-a-ethyl-;8 methyl-N-substituted aminoethanes.

EXAMPLE 24 1 p chlorobenzyl 2 methyl 5 methoxy 3 indolyla-ethyl 3 methyl ethylcyanide A solution of 0.042 mole of 2-methyl-5-methoxy-3- indolyl-u-ethyl-fi-methyl ethylcyanide in 40 ml. of dimethylformamide is added dropwise to a cold suspension of 0.044 mole of sodium hydride and 50 ml. of dimethylformamide. This mixture is stirred at room temperature for /2 hour, cooled, and treated with 0.044 mole of pchlorobenzoyl chloride and the reaction mixture stirred at room temperature for 16 hours. At the end of this reaction time, the mixture is poured into 500 m1. of ice water. The aqueous mixture is then extracted with (4 150 m1.) ether, and the ether extracts combined. The ether solution is then washed with ml. of potassium bicarbonate solution and 4X 75 ml. portions of water. The ether solution is then dried over sodium sulfate and concentrated in vacuo to yield 1-p-chlorobenz0yl-2- methyl 5 methoxy 3 indolyl-u-ethyl-fl-methyl ethylcyanide.

When the acylating agents obtained from Example 2 are used in place of the pchlorobenzoyl chloride in the above example, there are obtained the corresponding 1- acyI-Z-methyl-5-methoxy-3-indolyl-a-ethyl-fimethyl ethylcyanides.

Similarly, when the substituted-3-indolyl-u-ethyl-B-substituted ethylcyanides and 2-methyl-5-methoxy-3-indolylu-substituted-fl-methyl ethylcyanides obtained from Example 20 are used in place of 2-methyl-5-methoxy-3- indolyl-a-ethyl-fl-methyl ethylcyanide in the above example, there are obtained the corresponding l-p-chlorobenzoyl substituted-3-indolyl=a-ethyl- 3-substituted ethylcyanides and 1 p-chlorobenzoyl 2-methyl-5-methoxy-3- indolyl-a-substituted-fi-methyl ethylcyanides respectively.

(The compounds which contain groups which will be affected by acylation must be either protected or removed prior to acylation. Such groups are those which contain 1231:; active hydrogen, such as amino, carboxyl, and the 39 EXAMPLE 25 2 methyl methoxy 3 indolyl cc ethyl-fi-methylpropionaldehyde A solution of 0.05 mole of 2-methyl 5 methoxy- 3-indolyl-a-ethyl-li-methyl ethylcyanide and 0.1 mole of sodium hypophosphite in 40 ml. of 75% acetic acid is stirred with 2.0 grams of Raney nickel at 45 C. for 3 hours. The mixture is then filtered, the catalyst extracted with a small portion of warm aqueous alcohol, and the extract added to the filtrate. The filtrate is then diluted with 50 ml. of water and extracted with (3X 25 ml.) ether. The combined ether extracts are washed with (2X 15 ml.) Water, dried over sodium sulfate, and concentrated to yield 2-methyl-5-methoxy-3-indolyl-a-ethyl-B- methyl propionaldehyde. I

When the 3-indolyl-a-ethyl-fl-substituted ethylcyanides and 2 -methyl-S-methoxy-3-indolyl-a-substituted-B-methyl ethylcyanides obtained from Example 20 are used in place of 2-methyl-S-methoxy3-indolyl-a-ethyl-B-methyl ethylcyanide in the above example, there are obtained the corresponding propionaldehydes.

(The compounds which contain groups that will be affected by the above reduction are not used.)

EXAMPLE 26 N-ethyl-Z-methyl 5 methoxy 3 indolyl a ethyl- ,B-methyl propylimine A mixture of 0.03 mole of 2 methyl 5 methoxy 3- indolyl-a-ethyl-fl-methyl propionaldehyde in 200 ml. of ethylamine is stirred at room temperature for 2 hours. The solution is then concentrated in vacuo to yield crude N-ethyl-2methyl-5-methoxy-3-indolyl-a-ethyl p methyl propylimine.

When the substituted 3 indolyl-a-ethyl-fi-substituted propionaldehydes and 2 methyl 5-methoxy-3-indolyl-asubstituted-fl-methyl propionaldehydes obtained from Example 25 are used in place of 2-methyl-5-methoxy-3- indolyl oz ethyl-fl-methyl propionaldehyde in the above example, there are obtained the corresponding N-ethylimines.

EXAMPLE 27 N-ethyl-1-p-chl0robenz0yl-2-methyl-5-methoxy-3-ind0lylu-ethyl-B-methyl propylamine A solution of 0.042 mole of N-ethyl-Z-methyl-S- methoxy-3-indolyl-u-ethyl-B-methyl propylimine in 40 ml. of dimethylformarnide is added dropwise to a cold suspension of 2.0 grams of sodium hydride and 50 ml. of dimethylformamide. The mixture is stirred at room temperature for 20 minutes, cooled, and treated with (0.0444 mole) p-chlorobenzoyl chloride. The reaction mixture is stirred at room temperature for about 16 hours and poured into 500 ml. of ice water. The aqueous mixture is extractedwith four 200 ml. portions of ether. The ether extract is washed with 125 ml. of potassium bicarbonate solution and four 75 ml. portions of water. The ether layer is dried and concentrated at reduced pressure to give N-ethyl-1-p-chlorobenzoyl-2-methyl-5-methoxy-3- indolyl-a-ethyl-B-methyl propylimine.

When using the acylating agents obtained from Example 2 in place of p-chlorobenzoyl chloride in the above example, there are obtained the corresponding N-ethyl-lacyl 2 methyl 5-methoxy-3-indolyl-a-ethy1-B-methyl propylimines.

Similarly, when using the N-ethyl-substituted-3-indolyla-ethyl-B-substituted propylimines and N-ethyl-Z-methyl- 5 methoxy-3-indolylx-substituted-fi-methyl propylimines obtained from Exa-mple 26 in place of N-ethyl-Z-methyl- 5-methoxy-3-indolyl-a ethyl-fl-methyl propylimine in the above example, there are obtained the corresponding 1- p-chlorobenzoyl compounds. I

(Those compounds which contain groups that will be affected by the above acylation must be either protected or removed prior to acylation. Such groups may be represented as amino, carboxyl, and the like.)

EXAMPLE 28 2-methyl-5-methoxy-3-indolyl-a-ethyl-B-methylnitro-propl-ene A solution of 0.1 mole of 2-methyl-5-rnethoxy-3-indolyl-u-ethyl-fl-methyl propionaldehyde, 0.02 mole .of ammonium acetate, and 250 ml. of liquid nitromethane in a sealed vessel is stirred for 1 hour at 100 C. The reaction mixture is then cooled and 400 ml. of water are added. The 2 methyl 5 methoxy-3-indolyl-a-ethyl-p3- methyl-nitro-prop-l-ene, which crystallizes out, is filtered off and washed with (4x ml.) water. The indole is then recrystallized from chloroform-ethanol.

When. the substituted 3-indolyl-a-ethyl-[i-substituted propionaldehydes and 2-methyl-5-methoxy-3indolyl-etsubstituted-fi-methyl propionaldehydes obtained from Example 25 are used in. place of 2-methyl-5-methoxy-3-indolyl-a-ethyl-fi-methyl propionaldehyde in the above example, there are obtained the corresponding nitropropines.

EXAMPLE 29 1-p-chlorobenzoyl- Z-methyl-S-methoxy-3-indolyl-a-ethylp-methyl-nitro-propl-ene A solution of 0.021 mole of 2 methyl-5-methoxy-3-indolyl-u-ethyl-fl-methyl-nitro-prop-1-ene in 20 ml. of dimethylformamide is added dropwise to a cold suspension of 1.0 gram (0.022 mole) of sodium hydride (52% dispersion in mineral oil) and 25 ml. of dimethylformamide. The mixture is stirred at room temperature for 20 minutes, cooled, and treated with (0.0222 mole) of p-chlorobenzoyl chloride. The reaction mixture is stirred at room temperature for about 16 hours and poured into 260 ml. of ice water. The aqueous mixture is extracted with three 250 ml. portions of ether. The ether extract is washed with ml. of potassium bicarbonate solution and three 100 ml. portions of water. The ether solution is dried and concentrated at reduced pressure to a residue, which is then chromatographed on a column of silica gel using ether-petroleumether (v./v. 20-50%) as eluent to give 1- p chlorobenzoyl 2-methyl-5-methoxy-3indolyl-methylfl-methyl-nitro-prop-l-ene.

When the acylating agents obtained from Example 2 are used in place of the p-chlorobenzoyl chloride in the above example, there are obtained the corresponding 1- acyl 2 methyl S-methoxy-3-ind0lyl-a-ethyl-B-methylnitro-prop-l-enes.

Similarly, when the substituted-3-indolyl-a-ethyl-,8-substituted-nitro-prop-l-enes and 2-rnethyl-5-methoxy-3-indolyl a-substituted-fl-methyl-nitro-prop-l-enes obtained from Example 28 are used in place of the 2-methyl-S- methoxy 3-indolyl-u-ethyl-/8-methyl-nitro-prop-l-ene in the above example, there are obtained the corresponding 1 p-chlorobenzoyl-substituted-3-indolyl-a-ethyl-B-substituted-nitro-prop-l-enes and 1-p-chlorobenzoyl-2-methyl- 5 methoxy-3-indolyl-a-substituted-fl-methyl-hitro-prop-1- enes respectively.

(Those compounds which contain groups that will be affected by the above acylation must be protected or removed prior to acylation. Such groups may be represented as amino, carboxyl, and the like (containing active hydrogens).)

EXAMPLE 30 l-p-chlorobenzoyl-Z-methyl-3-benzylideneaminomethyl- S-methoxy indole A solution of 0.021 mole of 2-methyl-3-benzylideneaminomethyl-S-methoxy indole in 20 ml. of dimethylformamide is added dropwise to a cold suspension of 1.0 gram (0.022 mole) of sodium hydride (52% dispersion in mineral oil) and 25 ml. of dimethylformamide. The mixture is stirred at room temperature for 20 min- 

